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An overview of the c-MET signaling pathway:

An overview of the c-MET signaling pathway: Therapeutic Advances in Medical Oncology Review Shawna Leslie Organ and Ming-Sound Tsao Abstract: c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor, activates a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological conditions, it has also been found to be aberrantly acti- vated in human cancers via mutation, amplification or protein overexpression. This paper provides an overview of the c-MET signaling pathway, including its role in the development of cancers, and provides a rationale for targeting the pathway as a possible treatment option. Keywords: cancer, c-MET, hepatocyte growth factor (HGF), MET, signaling, receptor tyrosine kinase Receptor tyrosine kinases muscle and bone marrow, during both embryo- Receptor tyrosine kinases (RTKs) regulate many genesis and adulthood [Comoglio et al. 2008]. essential cellular processes in mammalian devel- opment, cell function and tissue homeostasis. The c-MET receptor is formed by proteolytic pro- However, although RTKs are important in cessing of a common precursor in the post-Golgi normal physiology, dysregulation of certain RTKs compartment into a single-pass, disulphide-linked has been implicated in the development and a/b heterodimer (Figure 1a.) [Trusolino and progression of many types of cancer [Krause and Comoglio, 2002]. The extracellular portion of Van Etten, 2005]. For example, expression of the c-MET is composed of three domain types. The c-MET RTK and its ligand, hepatocyte growth N-terminal 500 residues fold to form a large sema- factor (HGF), has been observed in tumor biop- phorin (Sema) domain, which encompasses the sies of most solid tumors and c-MET signal- whole a-subunit and part of the b-subunit. The ing has been documented in a wide range of Sema domain shares sequence homology with human malignancies [Peruzzi and Bottaro, 2006; domains found in the semaphorin and plexin fam- Birchmeier et al. 2003; Comoglio and Trusolino, ilies. The PSI domain (found in plexins, sema- 2002]. This paper provides an overview of the phorins and integrins) follows the Sema domain, c-MET signaling pathway, including its role in spans approximately 50 residues and includes the development of cancers, and provides a ratio- four disulphide bonds. This domain is connected nale for targeting the pathway as a possible treat- to the transmembrane helix via four immunoglob- ment option. ulinplexintranscription (IPT) domains, which are related to immunoglobulin-like domains and Hepatocyte growth factor and c-MET: are found in integrins, plexins and transcription structure and function factors. Intracellularly, the c-MET receptor con- The c-MET proto-oncogene is located on chro- tains a tyrosine kinase catalytic domain flanked by mosome 7q21-31. Its transcription is regulated distinctive juxtamembrane and carboxy-terminal by Ets (E-twenty six), Pax3 (paired box 3), AP2 sequences. (activator protein-2) and Tcf-4 (transcription factor 4) [Boon et al. 2002; Epstein et al. 1996; The ligand for c-MET was identified by two Gambarotta et al. 1996; Boccaccio et al. 1994], independent studies as both a motility factor and a scatter factor for hepatocytes, and this and it is expressed as multiple mRNA transcripts of 8, 7, 4.5, 3 and 1.5 kilobases [Park et al. 1986]. factor was later found to be the same molecule: The protein product of this gene is the c-MET HGF, also known as scatter factor (SF) [Weidner tyrosine kinase. This cell surface receptor is et al. 1991; Nakamura et al. 1989; Stoker et al. expressed in epithelial cells of many organs, 1987]. HGF acts as a pleiotropic factor and cyto- including the liver, pancreas, prostate, kidney, kine, promoting cell proliferation, survival, http://tam.sagepub.com S7 Therapeutic Advances in Medical Oncology 3 (1) (a) a-chain b-chain Sema domain ss PSI domain IPT domain Juxtamembrane Y1003 P domain Y1234 P Kinase domain Y1235 Y1349 Multifunctional docking site Y1356 P a-chain b-chain (b) R V K1 K2 K3 K4 Hairpin Kringle domains ss loop Figure 1. Domain structure of c-MET and hepatocyte growth factor (HGF). (a) The c-MET receptor is formed by proteolytic processing of a common precursor into a single-pass, disulphide-linked a/b heterodimer. The extra- cellular portion of c-MET is composed of three domain types. The N-terminal 500 residues fold to form a large semaphorin (Sema) domain, which encompasses the whole a-subunit and part of the b-subunit. The plex- insemaphorinintegrin (PSI) domain follows the Sema domain, spans approximately 50 residues and includes four disulphide bonds. This domain is connected to the transmembrane helix via four immunoglobu- linplexintranscription (IPT) domains, which are related to immunoglobulin-like domains. Intracellularly, the c-MET receptor contains a tyrosine kinase catalytic domain flanked by distinctive juxtamembrane and carboxy- terminal sequences. This portion of c-MET contains the catalytic tyrosines Y1234 and Y1235, which positively modulate enzyme activity, while the juxtamembrane tyrosine 1003 negatively regulates c-MET by recruiting the ubiquitin ligase casitas B-lineage lymphoma (c-CBL). The multifunctional docking site in the C-terminal tail con- tains tyrosines Y1349 and Y1356, which recruit several transducers and adaptors when c-MET is active. (b) The c-MET ligand, hepatocyte growth factor (HGF), is secreted by mesenchymal cells as a single-chain, biologically inert precursor and is converted into its bioactive form when extracellular proteases cleave the bond between Arg494 and Val495. The mature form of HGF consists of an a-and b-chain, which are held together by a disulphide bond. The a-chain contains an N-terminal hairpin loop followed by four kringle domains (80 amino acid double- looped structures formed by three internal disulphide bridges), K14. The b-chain is homologous to the serine proteases of the blood-clotting cascade, but lacks any proteolytic activity. Adapted from Comoglio et al. [2008]. motility, scattering, differentiation and morpho- et al. 1999], lung fibrosis [Watanabe et al. 2005] genesis [Basilico et al. 2008; Birchmeier et al. and progressive nephropathies [Liu and Yang, 2003; Trusolino and Comoglio, 2002]. In addi- 2006; Okada and Kalluri, 2005]. HGF is tion, HGF appears to play a protective role in secreted by mesenchymal cells as a single-chain, several diseases, including liver cirrhosis [Ueki biologically inert precursor and is converted into S8 http://tam.sagepub.com SL Organ and M-S Tsao its bioactive form when extracellular proteases 1995] and v-crk sarcoma virus CT10 oncogene cleave the bond between Arg494 and Val495. homolog (CRK) and CRK-like (CRKL) [Sakkab The mature form of HGF consists of an a- and et al. 2000; Garcia-Guzman et al. 1999], the effec- b-chain, which are held together by a disulphide tor molecules phosphatidylinositol 3-kinase bond. The a-chain contains an N-terminal hair- (PI3K), phospholipase Cg (PLCg) and v-src sar- pin loop followed by four kringle domains (80 coma (Schmidt-Ruppin A-2) viral oncogene amino acid double-looped structures formed by homolog (SRC) [Ponzetto et al. 1994], Src homol- three internal disulphide bridges). The b-chain ogy domain-containing 5’ inositol phosphatase is homologous to serine proteases of the blood- (SHIP-2) [Koch et al. 2005] and the transcription clotting cascade, but lacks proteolytic activity factor signal transducer and activator of transcrip- (Figure 1b). tion (STAT-3) [Zhang et al. 2002; Boccaccio et al. 1998] (Figure 2). In addition, unique to c-MET is Physiologically, c-MET is responsible for the its association with the adaptor protein GRB2- cell-scattering phenotype, as first demonstrated associated binding protein 1 (GAB1) [Weidner with MDCK cells treated with HGF [Zhu et al. et al. 1996], a multi-adaptor protein that, once 1994]. This process involves the disruption of bound to and phosphorylated by c-MET, creates cadherin-based cellcell contacts and subsequent binding sites for more downstream adaptors. cell motility, and is a key epithelial function in GAB1 can bind either directly to c-MET or indi- embryogenesis and wound repair [Corso et al. rectly, through GRB2. Additional tyrosines can 2005]. During embryogenesis, this motility func- also contribute to c-MET signaling. When Y1313 tion of c-MET is crucial for the long-range is phosphorylated, it binds and activates PI3K, migration of skeletal muscle progenitor cells. which probably promotes cell viability and motility Ablation of the MET or Hgf gene in mice results [Maulik et al. 2002a]. In addition, Y1365 regulates in the complete absence of all muscle groups cell morphogenesis when phosphorylated [Maulik derived from these cells [Bladt et al. 1995]. et al. 2002a]. During development, c-MET and HGF provide essential signals for survival and proliferation of The downstream response to c-MET activation hepatocytes and placental trophoblast cells; con- relies on stereotypical signaling modulators sequently, MET or Hgf knockout embryos show common to many RTKs. These pathways markedly reduced liver size. As well, altered pla- have been reviewed in detail [Trusolino et al. cental development in Hgf and MET knockout 2010], and are summarized in Figure 2. For mice is responsible for the death of these animals activation of the Mitogen activated protein in utero [Schmidt et al. 1995; Uehara et al. 1995]. kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral HGF/c-MET signaling oncogene homolog (RAS) guanine nucleotide The complex phenotype that results from c-MET exchanger Son of Sevenless (SOS) via binding signaling involves a number of molecular events, with SHC and GRB2 [Graziani et al. 1993], which have been described in detail in previous leading to the activation of RAS. This leads to reviews [Trusolino et al. 2010; Liu et al. 2008; the indirect activation of v-raf murine sarcoma Peruzzi and Bottaro, 2006; Birchmeier et al. viral oncogene homolog B1 (RAF) kinases, 2003; Maulik et al. 2002b]. HGF binding to c- which can subsequently activate the MAPK MET results in receptor homodimerization and effector kinase MEK and finally MAPK, phosphorylation of two tyrosine residues (Y1234 which can then translocate to the nucleus to and Y1235) located within the catalytic loop of activate transcription factors responsible for the tyrosine kinase domain [Rodrigues and Park, regulating a large number of genes. In the con- 1994]. Subsequently, tyrosines 1349 and 1356 in text of c-MET signaling, this results in pheno- the carboxy-terminal tail become phosphory- types such as cell proliferation, cell motility lated. These two tyrosines form a tandem SH2 and cell cycle progression [Paumelle et al. recognition motif unique to c-MET 2002; Fixman et al. 1996]. Src homology 2 1349 1356 (Y VHVX Y VNV) [Ponzetto et al. domain-containing phosphatase-2 (SHP2) can 1994]. When these tyrosines become phosphory- also link c-MET signaling to the MAPK cas- lated, they recruit signaling effectors that include cade, as sequestration of SHP2 to GAB1 is the adaptor proteins Growth factor receptor- responsible for extending the duration of bound protein 2 (GRB2) [Fixman et al. 1996], MAPK phosphorylation [Maroun et al. 2003; Src homology-2-containing (SHC) [Pelicci et al. Schaeer et al. 2000]. http://tam.sagepub.com S9 Therapeutic Advances in Medical Oncology 3 (1) HGF c-MET PTPs CBL Negative c-MET DAG PKC P P regulation PIP3 PP IP3 Ca PLCγ1 Src SHP2 Akt/PKB SOS Ras PI3K PP GRB2 SHC GRB2PP GAB1 SHC PLCγ1 FAK GAB1 STAT3 Raf PI3K SHP2 CRK CRK ERK/MAPK JNK Survival Gene expression changes Transformation Motility Proliferation Invasion Cell cycle progression Figure 2. c-MET signaling adaptors and mediators. When the tyrosines within the multifunctional docking site become phosphorylated they recruit signaling effectors, including the adaptor proteins growth factor receptor-bound protein 2 (GRB2), src homology 2 domain-containing (SHC), v-crk sarcoma virus CT10 oncogene homolog (CRK) and CRK-like (CRKL); the effector molecules phosphatidylinositol 3-kinase (PI3K), phospholipase Cg (PLCg) and SRC, the src homology 2 domain-containing 5’ inositol phosphatase SHIP-2, and the signal transducer and activator of transcription STAT3. In addition, unique to c-MET is its association with the adaptor protein GRB2-associated binding protein 1 (GAB1), a multi-adaptor protein that, once bound to and phosphorylated by c-MET, creates binding sites for more downstream adaptors. GAB1 can bind either directly to c-MET or indirectly, through GRB2. The downstream response to c-MET activation relies on stereotypical signaling modulators common to many receptor tyrosine kinases. For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. This leads to the indirect activation of v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which can subsequently activate MAPK effector kinase (MEK), and finally MAPK, which can then translocate to the nucleus to activate the transcription factors responsible for regulating a large number of genes, including those involved in cell proliferation, cell motility and cell cycle progression. SHP2 can also link c-MET signaling to the MAPK cascade, as sequestration of SHP2 to GAB1 is responsible for extending the duration of MAPK phosphorylation. The p85 subunit of PI3K can bind either directly to c-MET or indirectly through GAB1, which then signals through AKT/protein kinase B. This axis is primarily responsible for the cell survival response to c-MET signaling. Transformation downstream of the c-MET receptor is mediated by the phosphorylation of Janus kinase 1 (JNK), which occurs via binding to CRK. STAT3 has also been implicated in transformation. The direct binding of STAT3 to c-MET results in STAT3 phosphorylation, dimerization and its translocation to the nucleus. This has been shown to result in tubulogenesis and invasion. However, other reports have found that, although STAT3 is required for c-MET- mediated tumorigenesis, it has no effect on proliferation, invasion or branching morphogenesis. Cellular migration is also mediated downstream of c- MET by focal adhesion kinase (FAK), which is localized to cellular adhesion complexes. FAK is activated through phosphorylation by SRC family kinases, which have been shown to directly associate with c-MET. The c-METSRCFAK interaction leads to cell migration and the promotion of anchorage- independent growth. Negative regulation of the c-MET receptor is crucial for its tightly controlled activity. The Y1003 site, located in the juxtamembrane domain, is a negative regulatory site for c-MET signaling that acts by recruiting c-CBL. Regulation of c-MET signaling is also accomplished via its binding to various protein tyrosine phosphatases (PTPs). These PTPs modulate c-MET signaling by dephosphorylation of either the tyrosines in the c-MET kinase or the docking site. Finally, binding of PLCg to c-MET results in the activation of protein kinase C (PKC), which can then negatively regulate c-MET receptor phosphorylation and activity. Independently of PKC activation, an increase in intracellular calcium levels can also lead to negative c-MET regulation. Adapted from Trusolino et al. [2010] and Birchmeier et al. [2003]. DAG, diacylglycerol; HGF, hepatocyte growth factor; IP3, inositol triphos- phate; PIP3, phosphatidylinositol (3,4,5)-triphosphate. S10 http://tam.sagepub.com SL Organ and M-S Tsao The other major arm of c-MET signaling is the enhanced phosphatase 1 (dEP1) (or PTPrI) PI3K/Akt signaling axis. The p85 subunit of and leukocyte common antigen-related molecule PI3K can bind either directly to c-MET or indi- (LAR) (or PTPrF) [Machide et al. 2006; Palka rectly through GAB1, which then signals through et al. 2003], and the nonreceptor PTPs PTP1B AKT/protein kinase B. This axis is primarily and T-cell protein tyrosine phosphatase responsible for the cell survival response to (TCPTP) [Sangwan et al. 2008]. These PTPs c-MET signaling [Xiao et al. 2001]. modulate c-MET signaling by dephosphorylation Transformation downstream of the c-MET of either the tyrosines in the c-MET kinase receptor is mediated by the phosphorylation of domain (in the case of PTP1b and TCPTP) or Janus kinase 1 (JNK), which occurs via binding the docking tyrosines (in the case of dEP1). to CRK [Garcia-Guzman et al. 1999; Rodrigues Finally, binding of PLCg to c-MET results in et al. 1997]. STAT3 has also been implicated in the activation of protein kinase C (PKC), which transformation, although its proposed mecha- can then negatively regulate c-MET receptor nism is controversial. The direct binding of phosphorylation and activity [Gandino et al. STAT3 to c-MET results in STAT3 phosphory- 1994; Gandino et al. 1990]. Independently of lation, dimerization and its translocation to the PKC activation, an increase in intracellular cal- nucleus. This has been shown to result in tubu- cium levels can also lead to negative c-MET reg- logenesis [Boccaccio et al. 1998] and invasion ulation [Gandino et al. 1991]. [Syed et al. 2011]. However, other reports found that, although it is required for c-MET- Although the downstream response to c-MET is mediated tumorigenesis, it has no effect on pro- common to many RTKs, the potency, endurance liferation, invasion or branching morphogenesis and specificity of c-MET-triggered pathways is [Zhang et al. 2002]. Therefore, the role of secured by a network of upstream signaling co- STAT3 in c-MET signaling is probably context- receptors that physically associate with c-MET at and tissue-dependent. the cell surface (Figure 3) [Trusolino et al. 2010]. c-MET membrane partners can then amplify Cellular migration is also mediated downstream and/or diversify c-MET-dependent biochemical of c-MET by focal adhesion kinase (FAK), which inputs and translate them into meaningful (and is localized to cellular adhesion complexes. FAK specific) biological outcomes. For instance, the is activated through phosphorylation by SRC v6 splice variant of the hyaluronan receptor family kinases, which have been shown to associ- CD44 links c-MET signaling to the actin cyto- ate directly with c-MET [Ponzetto et al. 1994]. skeleton via GRB2 and the ezrin, radixin and The c-METSRCFAK interaction leads to cell moesin (ERM) family of proteins in order to migration and the promotion of anchorage-inde- recruit SOS, which then amplifies RAS-ERK sig- pendent growth [Hui et al. 2009; Rahimi et al. naling [Orian-Rousseau et al. 2007]. Recent work 1998]. In addition, SRC activation can positively has also shown that intercellular adhesion mole- feed back on c-MET activation [Organ et al. cule 1 (ICAM-1) can substitute for CD44v6 as a 2011; Hui et al. 2009]. Because of this, combi- co-receptor for c-MET in CD44v6 knockout natorial therapies involving both c-MET and mice, resulting in similar c-MET pathway activa- SRC inhibitors show promise in the treatment tion [Olaku et al. 2011]. As another example, c- of cancers dependent on either kinase [Sen MET binding to integrin a6b4 creates a supple- et al. 2011; Bertotti et al. 2010; Okamoto et al. mentary docking platform for binding of signal- 2010]. ing adaptors, leading to specific enhancement of PI3K, RAS and SRC activation [Trusolino et al. Negative regulation of the c-MET receptor is 2001; Bertotti et al. 2005]. In addition, the G- crucial for its tightly controlled activity, and can protein-coupled receptor (GPCR) agonists lyso- occur through a number of mechanisms. The phosphatidic acid (LPA), bradykinin, thrombin Y1003 site, located in the juxtamembrane and carbachol can induce c-MET phosphoryla- domain, is a negative regulatory site for c-MET tion [Fischer et al. 2004], although the functional signaling that acts by recruiting c-CBL (casitas consequences of these interactions are still B-lineage lymphoma) [Petrelli et al. 2002; unclear. Peschard et al. 2001]. Regulation of c-MET sig- naling is also accomplished via its binding to var- Crosstalk between c-MET and other RTKs has ious protein tyrosine phosphatases (PTPs), also been studied in great depth because of its including the receptor-type PTPs density potential importance in the development of http://tam.sagepub.com S11 actin Therapeutic Advances in Medical Oncology 3 (1) HGF HGF Ligand c-MET c-MET c-MET CD44/ICAM1 c-MET GPCR a6 b4 RTKs Agonist Integrin P PI3K SHP2 P P ERM P P P Src P SOS GRB2 SHC GRB2 SOS Amplification of Amplification of c-MET phosphorylation Ligand-independent RAS signaling RAS, Src, PI3K pathways and pathway activation transactivation of c-MET signaling Figure 3. c-MET transactivation. The potency and endurance of c-MET-triggered pathways is secured by a network of upstream signaling co-receptors that physically associate with c-MET at the cell surface. c-MET membrane partners can then amplify and/or diversify c-MET-dependent biochemical inputs and translate them into meaningful (and specific) biological outcomes. The v6 splice variant of the hyaluronan receptor CD44 links c-MET signaling to the actin cytoskeleton via the growth factor receptor-bound protein 2 (GRB2) and the ezrin, radixin, moesin (ERM) family of proteins in order to recruit son of sevenless (SOS), which then amplifies RAS- ERK signaling. Intercellular adhesion molecule 1 (ICAM-1) can substitute for CD44v6 as a co-receptor for c-MET in CD44v6 knockout mice, resulting in similar c-MET pathway activation. c-MET binding to integrin a6b4 creates a supplementary docking platform for the binding of signaling adaptors, leading to specific enhancement of phosphatidylinositol 3-kinase (PI3K), RAS and SRC activation. c- MET can also be activated by G-protein coupled receptors (GPCRs), although the functional outcome of this interaction is not well characterized. Crosstalk between c-MET and other receptor tyrosine kinases (RTKs) has also been studied in great depth because of its potential importance in the development of resistance to cancer therapeutics. Examples of these RTKs include the semaphorin receptors, the epidermal growth factor receptor (EGFR) family of receptors, the recepteur d’origine nantais (RON), platelet-derived growth factor receptor (PDGFR) and Axl; the list continues to grow. Adapted from Trusolino et al. [2010] and Corso et al. [2005] HGF, hepatocyte growth factor; SHC, src homolgy 2 domain-containing; SHP2, src homology 2 domain-containing phosphatase 2. resistance to cancer therapeutics [Lai et al. 2009]. c-MET interaction with the other EGFR family For instance, several members of the family of members ERBB2 and ERBB3 (for erythroblastic semaphorin receptors, including the plexins and leukemia viral oncogene homologs B2 and B3), neuropilins, can transactivate c-MET in the causing transactivation of both receptors absence of HGF when stimulated by their sema- [Bachleitner-Hofmann et al. 2008; Khoury et al. phorin ligands [Sierra et al. 2008; Hu et al. 2007; 2005]. Interaction of c-MET with the closely Conrotto et al. 2004]. c-MET has also been related RON (recepteur d’origine nantais) recep- shown by multiple studies to interact directly tor has also been shown to cause transphosphor- with the epidermal growth factor receptor ylation of the c-MET receptor in the absence of (EGFR), allowing activation of c-MET after HGF [Follenzi et al. 2000]. Interestingly, it was stimulation of cells with the EGFR ligands EGF recently shown that transactivation of RON by c- or transforming growth factor (TGF-a) [Jo et al. MET may be a feature of cancer cells that are 2000]. Stimulation of cells expressing both c- ‘addicted’ to c-MET signaling [Benvenuti et al. METand EGFR with EGF resulted in phosphor- 2011]. Recently, transactivation between c-Met ylation of c-MET, and stimulation with ligands and both platelet-derived growth factor receptor for both receptors resulted in synergistic activa- (PDGFR) and Axl was found to play a role in tion of downstream modulators, indicating bladder cancer [Yeh et al. 2011]. The list of cell mutual activation of these two pathways [Puri surface receptors that play a role in c-MET sig- and Salgia, 2008]. Evidence also exists for naling is growing constantly, and highlights the S12 http://tam.sagepub.com SL Organ and M-S Tsao importance of personally targeted cancer thera- suggesting that this genetic lesion can predispose pies, depending on the expression of these RTKs to the development of gastric carcinomas [Soman in specific patients. et al. 1991]. The c-MET receptor relies on its multitude of sig- Amplification of the c-MET gene, with conse- naling adaptors and cell surface co-receptors to quent protein overexpression and constitutive mediate biological responses unique to the recep- kinase activation, has been reported in a tor. Recent large-scale phosphoproteomic studies number of human primary tumors. These have provided even more insight into the intrica- include gastric and oesophageal carcinomas cies of the HGF/c-MET signaling axis [Organ [Miller et al. 2006; Hara et al. 1998; Kuniyasu et al. 2011; Hammond et al. 2010; Guo et al. et al. 1992; Houldsworth et al. 1990], medullo- 2008]. Although these studies identified the blastomas [Tong et al. 2004], and liver metastases highly conserved, core elements in c-MET signal- from colon carcinoma [Di Renzo et al. 1995c]. ing, they also identified tissue-specific differences, This last finding suggests that MET gene ampli- in addition to activation- compared with inhibi- fication can be acquired during the course of tion-specific differences, in downstream mediators tumor progression. Interestingly, recent research of c-MET. Although much work has been done has shown that non-small cell lung carcinomas since the discovery of the c-MET oncogene to with acquired resistance to EGFR inhibitors map out the details of c-MET signaling, this sug- tend to show amplifications in MET [Bean et al. gests that our understanding of the greater c-MET 2007; Engelman et al. 2007]. This suggests that network remains incomplete. combined treatment with EGFR and c-MET inhibitors could be necessary in a subset of HGF/c-MET signaling in cancer patients to circumvent the onset of resistance to As described above, c-MET signaling is an intri- these drugs. cate and highly regulated process. Mechanisms operating during tumor growth or cancer pro- The most convincing evidence that implicates gression have been identified that can result in c-MET in human cancers is provided by the acti- constitutive or prolonged activation of c-MET. vating mutations that were discovered in the Data collected from in vitro and in vivo tumor c-MET kinase domain in both sporadic and models suggest that these typically take place by inherited forms of human renal papillary carcino- means of three mechanisms: the occurrence of mas [Olivero et al. 1999; Schmidt et al. 1999]. specific genetic lesions, including translocations, Activating kinase domain mutations have subse- gene amplifications and activating mutations; by quently been identified in a small number of transcriptional upregulation of the c-MET pro- other cancers. Mutations have also been identi- tein in the absence of gene amplification; or via fied in the c-CBL binding site of the juxtamem- ligand-dependent autocrine or paracrine mecha- brane domain and in the HGF-binding region of nisms [Danilkovitch-Miagkova and Zbar, 2002]. the Sema domain [Forbes et al. 2008]. In hered- itary cancers, heterozygous mutations are usually c-MET was originally identified as an oncogene accompanied by trisomy of the whole chromo- in the 1980s [Cooper et al. 1984], isolated first some 7, suggesting that when only a single from a human osteosarcoma cell line treated with allele is mutated the mutation must be present the carcinogen N-methyl-N-nitro-N-nitrosogua- in multiple copies to produce the full trans- nidine. The c-MET identified in this cell line formed phenotype [Schmidt et al. 1997]. contained a chromosomal rearrangement that fused the tyrosine kinase domain of the c-MET Increased protein expression as a consequence of proto-oncogene to an upstream translocating transcriptional upregulation in the absence promoter region (TPR). This rearrangement of gene amplification is the most frequent cause caused constitutive dimerization and therefore of constitutive c-MET activation in human activation of the encoded protein [Park et al. tumors [Comoglio et al. 2008], and has been 1986]. Expression of TPR-MET in transgenic reported in an ever growing number of carcino- mice resulted in the development of multiple mas, including thyroid [Di Renzo et al. 1992; Di epithelial-derived tumors [Liang et al. 1996]. In Renzo et al. 1995b], colorectal [Hiscox et al. humans, the TPR-MET translocation has been 1997; Di Renzo et al. 1995a; Liu et al. 1992], found in both the precursor lesions of gastric can- ovarian [Di Renzo et al. 1994], pancreatic [Di cers and in the adjacent normal mucosa, Renzo et al. 1995b; Furukawa et al. 1995], lung http://tam.sagepub.com S13 Therapeutic Advances in Medical Oncology 3 (1) [Nakamura et al. 2008; Tsao et al. 1998] and continues to strongly suggest that amplification breast [Lengyel et al. 2005], to name a few. of the MET gene might be a genetic predictor of Hypoxia, caused by lack of oxygen diffusion to therapeutic responsiveness [Lutterbach et al. the centre of a growing tumor, is one mechanism 2007; Smolen et al. 2006]. that has been demonstrated to activate c-MET transcription in vitro and in vivo [Pennacchietti ‘Oncogene expedience’ is a tumor-specific term et al. 2003]. Hypoxia activates the c-MET pro- that describes the scattering, invasion and sur- moter, via the transcription factor hypoxia induc- vival of cancer cells associated with metastatic ible factor 1a (HIF1a), which itself is regulated spreading [Comoglio et al. 2008]. In contrast to by the concentration of intracellular oxygen oncogene addiction, the inappropriate activation [Kitajima et al. 2008]. of c-MET resulting in oncogene expedience is the consequence rather than the cause of the trans- Although c-MET activation via a ligand-depen- formed phenotype. Thus, activation of c-MET is dent autocrine or paracrine loop will be fully dis- a secondary event in various types of tumor, exac- cussed elsewhere in this supplement, we will erbating the malignant properties of already touch on it briefly here. HGF is expressed ubiq- transformed cells. In these cases, aberrant c- uitously within the body and has been found to MET activation occurs through a number of pos- be frequently overexpressed in the reactive sible routes; these include transcriptional upregu- stroma of primary tumors [Matsumoto and lation by other oncogenes [Abounader et al. Nakamura, 2006]. This supports the formation 2004; Ivan et al. 1997], environmental conditions of paracrine positive feedback loops, which in such as hypoxia [Pennacchietti et al. 2003] and turn can support the dissemination of cancer agents secreted by reactive stroma such as inflam- cells to distant locations. The autocrine stimula- matory cytokines, proangiogenic factors and tion of c-MET has also been identified in cancer HGF itself [Bhowmick et al. 2004; Boccaccio cells [Rahimi et al. 1996; Rong and Vande et al. 1994]. Woude, 1994], and appears to be indicative of increased aggressiveness of tumors along with As MET is a necessary oncogene for a number of poor prognostic signs in cancer patients [Navab neoplasms, targeted therapies against c-MET et al. 2009; Vadnais et al. 2002; Tuck et al. 1996]. could be effective as a front-line intervention to treat a limited subset of c-MET-addicted c-MET as a target for therapeutic inhibition tumors and subsequent c-MET-addicted metas- Although the development of c-MET inhibitors tases [Comoglio et al. 2008]. In addition, as MET will be discussed elsewhere in this supplement, also acts as an adjuvant prometastatic gene here we consider the dual role c-MET plays for many neoplasms, targeted therapies against in both the development and progression of c-MET could also be used as a secondary cancers, and how each could be targeted by approach to hamper the progression of a much c-MET inhibitors. wider spectrum of advanced cancers that rely on c-MET activation for metastatic spreading. Some tumors appear to be dependent on (or ‘addicted’ to) sustained c-MET activity for their Summary and conclusions growth and survival, and this is often associated The HGF/c-MET pathway comprises a complex with MET gene amplification. This phenomenon and unique signaling network and plays a pivotal is known as ‘oncogene addiction’ and applies to all role in both normal development and cancer pro- settings where cancer cells appear to be dependent gression. c-MET controls multiple biological on a single overactive oncogene for their prolifer- functions, including proliferation, survival, motil- ation and survival [Sharma et al. 2007; Sharma ity and invasion, which, when dysregulated by and Settleman, 2007]. Oncogene addiction was aberrant c-MET activation, can lead to both identified after studies using EGFR tyrosine tumor growth and metastatic progression of kinase inhibitors demonstrated that these inhibi- cancer cells. Consequently, c-MET is a versatile tors were efficacious only in a small subset of candidate for targeted therapeutic intervention. tumors which exhibited genetic alterations of the receptor itself [Sharma et al. 2007]. Although this Acknowledgement c-MET-addicted phenotype has only recently been Matthew Joynson, a medical writer, assisted with (yet consistently) described in cultured cells from the styling of this manuscript. The authors wrote gastric and non-small cell lung carcinomas, it and revised the main draft of the article. S14 http://tam.sagepub.com SL Organ and M-S Tsao Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A. Funding and Birchmeier, C. (1995) Essential role for the c-met This study was supported by the Canadian receptor in the migration of myogenic precursor cells Institutes of Health Research (grant number into the limb bud. Nature 376: 768771. MOP-64345) and in part by the Ontario Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Ministry of Health and Long Term Care. SLO Michieli, P., Battistini, C. et al. (1998) Induction of is supported by the CIHR Banting and Best epithelial tubules by growth factor HGF depends on Doctoral Research Award. MST is the M. the STAT pathway. Nature 391: 285288. Qasim Choksi Chair in Lung Cancer Boccaccio, C., Gaudino, G., Gambarotta, G., Galimi, Translational Research. Editorial assistance was F. and Comoglio, P.M. (1994) Hepatocyte growth funded by Daiichi Sankyo Europe GmbH. factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. J Biol Chem 269: 1284612851. Conflict of interest statement Shawna L. Organ declares no conflict of interest. Boon, E.M., van der Neut, R., van de Wetering, M., Dr Ming-Sound Tsao has received honoraria Clevers, H. and Pals, S.T. (2002) Wnt signaling reg- from Daiichi Sankyo Europe GmbH for speaking ulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res 62: 51265128. at scientific symposia. Comoglio, P.M., Giordano, S. and Trusolino, L. (2008) Drug development of MET inhibitors: target- ing oncogene addiction and expedience. Nat Rev Drug References Discov 7: 504516. Abounader, R., Reznik, T., Colantuoni, C., Martinez- Murillo, F., Rosen, E.M. and Laterra, J. (2004) Comoglio, P.M. and Trusolino, L. (2002) Invasive Regulation of c-Met-dependent gene expression by growth: from development to metastasis. J Clin Invest PTEN. Oncogene 23: 91739182. 109: 857862. Bachleitner-Hofmann, T., Sun, M.Y., Chen, C.T., Conrotto, P., Corso, S., Gamberini, S., Comoglio, Tang, L., Song, L., Zeng, Z. et al. (2008) HER kinase P.M. and Giordano, S. (2004) Interplay between activation confers resistance to MET tyrosine kinase scatter factor receptors and B plexins controls invasive inhibition in MET oncogene-addicted gastric cancer growth. Oncogene 23: 51315137. cells. Mol Cancer Ther 7: 34993508. Cooper, C.S., Park, M., Blair, D.G., Tainsky, M.A., Basilico, C., Arnesano, A., Galluzzo, M., Comoglio, Huebner, K., Croce, C.M. et al. (1984) Molecular P.M. and Michieli, P. (2008) A high affinity hepatocyte cloning of a new transforming gene from a chemically growth factor-binding site in the immunoglobulin-like transformed human cell line. Nature 311: 2933. region of Met. J Biol Chem 283: 2126721277. Corso, S., Comoglio, P.M. and Giordano, S. (2005) Bean, J., Brennan, C., Shih, J.Y., Riely, G., Viale, A., Cancer therapy: can the challenge be MET? Trends Wang, L. et al. (2007) MET amplification occurs with Mol Med 11: 284292. or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erloti- Danilkovitch-Miagkova, A. and Zbar, B. (2002) nib. Proc Natl Acad Sci USA 104: 2093220937. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 109: 863867. Benvenuti, S., Lazzari, L., Arnesano, A., Li Chiavi, G., Gentile, A. and Comoglio, P.M. (2011) Ron kinase Di Renzo, M.F., Olivero, M., Ferro, S., Prat, M., transphosphorylation sustains MET oncogene addic- Bongarzone, I., Pilotti, S. et al. (1992) Overexpression tion. Cancer Res 71: 19451955. of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7: 25492553. Bertotti, A., Bracco, C., Girolami, F., Torti, D., Gastaldi, S., Galimi, F. et al. (2010) Inhibition of Src Di Renzo, M.F., Olivero, M., Giacomini, A., Porte, impairs the growth of met-addicted gastric tumors. H., Chastre, E., Mirossay, L. et al. (1995a) Clin Cancer Res 16: 39333943. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal Bertotti, A., Comoglio, P.M. and Trusolino, L. (2005) cancer. Clinical Cancer Res 1: 147154. Beta4 integrin is a transforming molecule that unleashes Met tyrosine kinase tumorigenesis. Cancer Di Renzo, M.F., Olivero, M., Katsaros, D., Crepaldi, Res 65: 1067410679. T., Gaglia, P., Zola, P. et al. (1994) Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer Bhowmick, N.A., Neilson, E.G. and Moses, H.L. 58: 658662. (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432: 332337. Di Renzo, M.F., Olivero, M., Serini, G., Orlandi, F., Pilotti, S., Belfiore, A. et al. (1995b) Overexpression of Birchmeier, C., Birchmeier, W., Gherardi, E. and the c-MET/HGF receptor in human thyroid carcino- Vande Woude, G.F. (2003) Met, metastasis, mas derived from the follicular epithelium. J Endocrinol motility and more. Nat Rev Mol Cell Biol Invest 18: 134139. 4: 915925. http://tam.sagepub.com S15 Therapeutic Advances in Medical Oncology 3 (1) Di Renzo, M.F., Poulsom, R., Olivero, M., Comoglio, Graziani, A., Gramaglia, D., dalla Zonca, P. and P.M. and Lemoine, N.R. (1995c) Expression of the Comoglio, P.M. (1993) Hepatocyte growth Met/hepatocyte growth factor receptor in human factor/scatter factor stimulates the Ras-guanine pancreatic cancer. Cancer Res 55: 11291138. nucleotide exchanger. J Biol Chem 268: 91659168. Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O. et al. (2007) MET amplifi- Guo, A., Villen, J., Kornhauser, J., Lee, K.A., Stokes, cation leads to gefitinib resistance in lung cancer by M.P., Rikova, K. et al. (2008) Signaling networks activating ERBB3 signaling. Science 316: 10391043. assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105: 692697. Epstein, J.A., Shapiro, D.N., Cheng, J., Lam, P.Y. and Maas, R.L. (1996) Pax3 modulates expression of the Hammond, D.E., Hyde, R., Kratchmarova, I., c-Met receptor during limb muscle development. Proc Beynon, R.J., Blagoev, B. and Clague, M.J. (2010) Natl Acad Sci USA 93: 42134218. Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks. J Proteome Res Fischer, O.M., Giordano, S., Comoglio, P.M. and 9: 27342742. Ullrich, A. (2004) Reactive oxygen species mediate Met receptor transactivation by G protein-coupled Hara, T., Ooi, A., Kobayashi, M., Mai, M., receptors and the epidermal growth factor receptor in Yanagihara, K. and Nakanishi, I. (1998) Amplification human carcinoma cells. J Biol Chem of c-myc, K-sam, and c-met in gastric cancers: detec- 279: 2897028978. tion by fluorescence in situ hybridization. Lab Invest 78: 11431153. Fixman, E.D., Fournier, T.M., Kamikura, D.M., Naujokas, M.A. and Park, M. (1996) Pathways Hiscox, S.E., Hallett, M.B., Puntis, M.C., Nakamura, downstream of Shc and Grb2 are required for cell T. and Jiang, W.G. (1997) Expression of the HGF/SF transformation by the tpr-Met oncoprotein. J Biol receptor, c-met, and its ligand in human colorectal Chem 271: 1311613122. cancers. Cancer Invest 15: 513521. Follenzi, A., Bakovic, S., Gual, P., Stella, M.C., Houldsworth, J., Cordon-Cardo, C., Ladanyi, M., Longati, P. and Comoglio, P.M. (2000) Cross-talk Kelsen, D.P. and Chaganti, R.S. (1990) Gene ampli- between the proto-oncogenes Met and Ron. Oncogene fication in gastric and esophageal adenocarcinomas. 19: 30413049. Cancer Res 50: 64176422. Forbes, S.A., Bhamra, G., Bamford, S., Dawson, E., Hu, B., Guo, P., Bar-Joseph, I., Imanishi, Y., Jarzynka, Kok, C., Clements, J. et al. (2008) The Catalogue of M.J., Bogler, O. et al. (2007) Neuropilin-1 promotes Somatic Mutations in Cancer (COSMIC). Curr human glioma progression through potentiating the Protoc Hum Genet Chapter 10, Unit 10.11. activity of the HGF/SF autocrine pathway. Oncogene 26: 55775586. Furukawa, T., Duguid, W.P., Kobari, M., Matsuno, S. and Tsao, M.S. (1995) Hepatocyte growth factor and Hui, A.Y., Meens, J.A., Schick, C., Organ, S.L., Qiao, Met receptor expression in human pancreatic carci- H., Tremblay, E.A. et al. (2009) Src and FAK mediate nogenesis. Am J Pathol 147: 889895. cell-matrix adhesion-dependent activation of Met during transformation of breast epithelial cells. J Cell Gambarotta, G., Boccaccio, C., Giordano, S., Ando, Biochem 107: 11681181. M., Stella, M.C. and Comoglio, P.M. (1996) Ets up- regulates MET transcription. Oncogene Ivan, M., Bond, J.A., Prat, M., Comoglio, P.M. and 13: 19111917. Wynford-Thomas, D. (1997) Activated ras and ret oncogenes induce over-expression of c-met (hepato- Gandino, L., Di Renzo, M.F., Giordano, S., cyte growth factor receptor) in human thyroid epithe- Bussolino, F. and Comoglio, P.M. (1990) Protein lial cells. Oncogene 14: 24172423. kinase-c activation inhibits tyrosine phosphorylation of the c-met protein. Oncogene 5: 721725. Jo, M., Stolz, D.B., Esplen, J.E., Dorko, K., Michalopoulos, G.K. and Strom, S.C. (2000) Gandino, L., Longati, P., Medico, E., Prat, M. and Cross-talk between epidermal growth factor receptor Comoglio, P.M. (1994) Phosphorylation of serine 985 and c-Met signal pathways in transformed cells. J Biol negatively regulates the hepatocyte growth factor Chem 275: 88068811. receptor kinase. J Biol Chem 269: 18151820. Khoury, H., Naujokas, M.A., Zuo, D., Sangwan, V., Gandino, L., Munaron, L., Naldini, L., Ferracini, R., Frigault, M.M., Petkiewicz, S. et al. (2005) HGF Magni, M. and Comoglio, P.M. (1991) Intracellular converts ErbB2/Neu epithelial morphogenesis to cell calcium regulates the tyrosine kinase receptor encoded invasion. Mol Biol Cell 16: 550561. by the MET oncogene. J Biol Chem 266: 1609816104. Kitajima, Y., Ide, T., Ohtsuka, T. and Miyazaki, K. (2008) Induction of hepatocyte growth factor activator Garcia-Guzman, M., Dolfi, F., Zeh, K. and Vuori, K. gene expression under hypoxia activates the hepatocyte (1999) Met-induced JNK activation is mediated by the growth factor/c-Met system via hypoxia inducible adapter protein Crk and correlates with the Gab1 - Crk factor-1 in pancreatic cancer. Cancer Science signaling complex formation. Oncogene 99: 13411347. 18: 77757786. S16 http://tam.sagepub.com SL Organ and M-S Tsao Koch, A., Mancini, A., El Bounkari, O. and Tamura, tumor-stromal interactions. Int J Cancer T. (2005) The SH2-domain-containing inositol 5- 119: 477483. phosphatase (SHIP)-2 binds to c-Met directly via Maulik, G., Madhiwala, P., Brooks, S., Ma, P.C., tyrosine residue 1356 and involves hepatocyte growth Kijima, T., Tibaldi, E.V. et al. (2002a) Activated c-Met factor (HGF)-induced lamellipodium formation, cell signals through PI3K with dramatic effects on cyto- scattering and cell spreading. Oncogene skeletal functions in small cell lung cancer. J Cell Mol 24: 34363447. Med 6: 539553. Krause, D.S. and Van Etten, R.A. (2005) Tyrosine Maulik, G., Shrikhande, A., Kijima, T., Ma, P.C., kinases as targets for cancer therapy. N Engl J Med Morrison, P.T. and Salgia, R. (2002b) Role of the 353: 172187. hepatocyte growth factor receptor, c-Met, in onco- Kuniyasu, H., Yasui, W., Kitadai, Y., Yokozaki, H., Ito, genesis and potential for therapeutic inhibition. H. and Tahara, E. (1992) Frequent amplification of Cytokine Growth Factor Rev 13: 4159. the c-met gene in scirrhous type stomach cancer. Miller, C.T., Lin, L., Casper, A.M., Lim, J., Thomas, Biochem Biophys Res Commun 189: 227232. D.G., Orringer, M.B. et al. (2006) Genomic amplifi- Lai, A.Z., Abella, J.V. and Park, M. (2009) Crosstalk cation of MET with boundaries within fragile site in Met receptor oncogenesis. Trends Cell Biol FRA7G and upregulation of MET pathways in 19: 542551. esophageal adenocarcinoma. Oncogene 25: 409418. Lengyel, E., Prechtel, D., Resau, J.H., Gauger, K., Nakamura, T., Nishizawa, T., Hagiya, M., Seki, T., Welk, A., Lindemann, K. et al. (2005) C-Met overex- Shimonishi, M., Sugimura, A. et al. (1989) Molecular pression in node-positive breast cancer identifies cloning and expression of human hepatocyte growth patients with poor clinical outcome independent of factor. Nature 342: 440443. Her2/neu. Int J Cancer 113: 678682. Nakamura, Y., Matsubara, D., Goto, A., Ota, S., Liang, T.J., Reid, A.E., Xavier, R., Cardiff, R.D. and Sachiko, O., Ishikawa, S. et al. (2008) Constitutive Wang, T.C. (1996) Transgenic expression of tpr-met activation of c-Met is correlated with c-Met overex- oncogene leads to development of mammary hyper- pression and dependent on cell-matrix adhesion in plasia and tumors. J Clin Invest 97: 28722877. lung adenocarcinoma cell lines. Cancer Sci 99: 1422. Liu, C., Park, M. and Tsao, M.S. (1992) Navab, R., Liu, J., Seiden-Long, I., Shih, W., Li, M., Overexpression of c-met proto-oncogene but not epi- Bandarchi, B. et al. (2009) Co-overexpression of Met dermal growth factor receptor or c-erbB-2 in primary and hepatocyte growth factor promotes systemic human colorectal carcinomas. Oncogene 7: 181185. metastasis in NCI-H460 non-small cell lung carci- noma cells. Neoplasia 11: 12921300. Liu, X., Yao, W., Newton, R.C. and Scherle, P.A. (2008) Targeting the c-MET signaling pathway for Okada, H. and Kalluri, R. (2005) Cellular and cancer therapy. Expert Opin Investig Drugs molecular pathways that lead to progression and 17: 9971011. regression of renal fibrogenesis. Curr Mol Med 5: 467474. Liu, Y. and Yang, J. (2006) Hepatocyte growth factor: new arsenal in the fights against renal fibrosis? Kidney Okamoto, W., Okamoto, I., Yoshida, T., Okamoto, K., Int 70: 238240. Takezawa, K., Hatashita, E. et al. (2010) Identification of c-Src as a potential therapeutic target for gas- Lutterbach, B., Zeng, Q., Davis, L.J., Hatch, H., tric cancer and of MET activation as a cause of resis- Hang, G., Kohl, N.E. et al. (2007) Lung cancer cell tance to c-Src inhibition. Mol Cancer Ther lines harboring MET gene amplification are dependent 9: 11881197. on Met for growth and survival. Cancer Res 67: 20812088. Olaku, V., Matzke, A., Mitchell, C., Hasenauer, S., Sakkaravarthi, A., Pace, G. et al. (2011) c-Met recruits Machide, M., Hashigasako, A., Matsumoto, K. and ICAM-1 as a co-receptor to compensate for the loss of Nakamura, T. (2006) Contact inhibition of hepatocyte CD44 in the Cd44 null mice. Mol Biol Cell growth regulated by functional association of the 22: 27772786. c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. J Biol Chem Olivero, M., Valente, G., Bardelli, A., Longati, P., 281: 87658772. Ferrero, N., Cracco, C. et al. (1999) Novel mutation in the ATP-binding site of the MET oncogene tyrosine Maroun, C.R., Naujokas, M.A. and Park, M. (2003) kinase in a HPRCC family. Int J Cancer 82: 640643. Membrane targeting of Grb2-associated binder-1 (Gab1) scaffolding protein through Src myristoylation Organ, S.L., Tong, J., Taylor, P., St-Germain, J.R., sequence substitutes for Gab1 pleckstrin homology Navab, R., Moran, M.F. et al. (2011) Quantitative domain and switches an epidermal growth factor phospho-proteomic profiling of hepatocyte growth response to an invasive morphogenic program. factor (HGF)-MET signaling in colorectal cancer. Mol Biol Cell 14: 16911708. J Proteome Res 10: 32003211. Matsumoto, K. and Nakamura, T. (2006) Hepatocyte Orian-Rousseau, V., Morrison, H., Matzke, A., growth factor and the Met system as a mediator of Kastilan, T., Pace, G., Herrlich, P. et al. (2007) http://tam.sagepub.com S17 Therapeutic Advances in Medical Oncology 3 (1) Hepatocyte growth factor-induced Ras activation and oncogenic potential of the Met receptor tyrosine requires ERM proteins linked to both CD44v6 and kinase. Oncogene 9: 20192027. F-actin. Mol Biol Cell 18: 7683. Rodrigues, G.A., Park, M. and Schlessinger, J. (1997) Activation of the JNK pathway is essential for trans- Palka, H.L., Park, M. and Tonks, N.K. (2003) formation by the Met oncogene. EMBO J Hepatocyte growth factor receptor tyrosine kinase met 16: 26342645. is a substrate of the receptor protein-tyrosine phos- phatase DEP-1. J Biol Chem 278: 57285735. Rong, S. and Vande Woude, G.F. (1994) Autocrine mechanism for met proto-oncogene tumorigenicity. Park, M., Dean, M., Cooper, C.S., Schmidt, M., Cold Spring Harbor Symp Quant Biol 59: 629636. O’Brien, S.J., Blair, D.G. et al. (1986) Mechanism of met oncogene activation. Cell 45: 895904. Sakkab, D., Lewitzky, M., Posern, G., Schaeper, U., Sachs, M., Birchmeier, W. et al. (2000) Signaling of Paumelle, R., Tulasne, D., Kherrouche, Z., Plaza, S., hepatocyte growth factor/scatter factor (HGF) to the Leroy, C., Reveneau, S. et al. (2002) Hepatocyte small GTPase Rap1 via the large docking protein Gab1 growth factor/scatter factor activates the ETS1 tran- and the adapter protein CRKL. J Biol Chem scription factor by a RAS-RAF-MEK-ERK signaling 275: 1077210778. pathway. Oncogene 21: 23092319. Sangwan, V., Paliouras, G.N., Abella, J.V., Dube, N., Pelicci, G., Giordano, S., Zhen, Z., Salcini, A.E., Monast, A., Tremblay, M.L. et al. (2008) Regulation Lanfrancone, L., Bardelli, A. et al. (1995) The moto- of the Met receptor-tyrosine kinase by the protein- genic and mitogenic responses to HGF are amplified tyrosine phosphatase 1B and T-cell phosphatase. J Biol by the Shc adaptor protein. Oncogene 10: 16311638. Chem 283: 3437434383. Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., M., Giordano, S. and Comoglio, P.M. (2003) Hypoxia Kempkes, B. and Birchmeier, W. (2000) Coupling of promotes invasive growth by transcriptional activation Gab1 to c-Met, Grb2, and Shp2 mediates biological of the met protooncogene. Cancer Cell 3: 347361. responses. J Cell Biol 149: 14191432. Peruzzi, B. and Bottaro, D.P. (2006) Targeting the c- Schmidt, C., Bladt, F., Goedecke, S., Brinkmann, V., Met signaling pathway in cancer. Clin Cancer Res Zschiesche, W., Sharpe, M. et al. (1995) Scatter factor/ 12: 36573660. hepatocyte growth factor is essential for liver develop- ment. Nature 373: 699702. Peschard, P., Fournier, T.M., Lamorte, L., Naujokas, M.A., Band, H., Langdon, W.Y. et al. (2001) Mutation Schmidt, L., Duh, F.M., Chen, F., Kishida, T., Glenn, of the c-Cbl TKB domain binding site on the Met G., Choyke, P. et al. (1997) Germline and somatic receptor tyrosine kinase converts it into a transforming mutations in the tyrosine kinase domain of the MET protein. Mol Cell 8: 9951004. proto-oncogene in papillary renal carcinomas. Nat Genet 16: 6873. Petrelli, A., Gilestro, G.F., Lanzardo, S., Comoglio, P.M., Migone, N. and Giordano, S. (2002) The Schmidt, L., Junker, K., Nakaigawa, N., Kinjerski, T., endophilin-CIN85-Cbl complex mediates ligand- Weirich, G., Miller, M. et al. (1999) Novel mutations dependent downregulation of c-Met. Nature of the MET proto-oncogene in papillary renal carci- 416: 187190. nomas. Oncogene 18: 23432350. Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Sen, B., Peng, S., Saigal, B., Williams, M.D. and Zonca, P., Giordano, S. et al. (1994) A multifunctional Johnson, F.M. (2011) Distinct interactions between c- docking site mediates signaling and transformation by Src and c-Met in mediating resistance to c-Src inhi- the hepatocyte growth factor/scatter factor receptor bition in head and neck cancer. Clin Cancer Res family. Cell 77: 261271. 17: 514524. Puri, N. and Salgia, R. (2008) Synergism of EGFR Sharma, S.V., Bell, D.W., Settleman, J. and Haber, and c-Met pathways, cross-talk and inhibition, in non- D.A. (2007) Epidermal growth factor receptor muta- small cell lung cancer. J Carcinog 7: 9. tions in lung cancer. Nat Rev Cancer 7: 169181. Rahimi, N., Hung, W., Tremblay, E., Saulnier, R. and Sharma, S.V. and Settleman, J. (2007) Oncogene Elliott, B. (1998) c-Src kinase activity is required for addiction: setting the stage for molecularly targeted hepatocyte growth factor-induced motility and cancer therapy. Genes Dev 21: 32143231. anchorage-independent growth of mammary carci- Sierra, J.R., Corso, S., Caione, L., Cepero, V., noma cells. J Biol Chem 273: 3371433721. Conrotto, P., Cignetti, A. et al. (2008) Tumor angio- Rahimi, N., Tremblay, E., McAdam, L., Park, M., genesis and progression are enhanced by Sema4D Schwall, R. and Elliott, B. (1996) Identification produced by tumor-associated macrophages. J Exp of a hepatocyte growth factor autocrine loop in a Med 205: 16731685. murine mammary carcinoma. Cell Growth Differ Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., 7: 263270. Barmettler, A., Archibald, H. et al. (2006) Rodrigues, G.A. and Park, M. (1994) Amplification of MET may identify a subset of cancers Autophosphorylation modulates the kinase activity with extreme sensitivity to the selective tyrosine kinase S18 http://tam.sagepub.com SL Organ and M-S Tsao inhibitor PHA-665752. Proc Natl Acad Sci USA Ueki, T., Kaneda, Y., Tsutsui, H., Nakanishi, K., 103: 23162321. Sawa, Y., Morishita, R. et al. (1999) Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Soman, N.R., Correa, P., Ruiz, B.A. and Wogan, G.N. Med 5: 226230. (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and Vadnais, J., Nault, G., Daher, Z., Amraei, M., Dodier, precursor lesions. Proc Natl Acad Sci USA Y., Nabi, I.R. et al. (2002) Autocrine activation of the 88: 48924896. hepatocyte growth factor receptor/met tyrosine kinase induces tumor cell motility by regulating pseudopodial Stoker, M., Gherardi, E., Perryman, M. and Gray, J. protrusion. J Biol Chem 277: 4834248350. (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327: 239242. Watanabe, M., Ebina, M., Orson, F.M., Nakamura, A., Kubota, K., Koinuma, D. et al. (2005) Hepatocyte Syed, Z.A., Yin, W., Hughes, K., Gill, J.N., Shi, R. and growth factor gene transfer to alveolar septa for effec- Clifford, J.L. (2011) HGF/c-met/Stat3 signaling tive suppression of lung fibrosis. Mol Ther 12: 5867. during skin tumor cell invasion: indications for a pos- itive feedback loop. BMC Cancer 11: 180. Weidner, K.M., Arakaki, N., Hartmann, G., Vandekerckhove, J., Weingart, S., Rieder, H. et al. Tong, C.Y., Hui, A.B., Yin, X.L., Pang, J.C., Zhu, (1991) Evidence for the identity of human scatter X.L., Poon, W.S. et al. (2004) Detection of oncogene factor and human hepatocyte growth factor. Proc Natl amplifications in medulloblastomas by comparative Acad Sci USA 88: 70017005. genomic hybridization and array-based comparative genomic hybridization. J Neurosurg 100(2 Suppl Weidner, K.M., Di Cesare, S., Sachs, M., Brinkmann, Pediatrics): 187193. V., Behrens, J. and Birchmeier, W. (1996) Interaction between Gab1 and the c-Met receptor tyrosine kinase Trusolino, L., Bertotti, A. and Comoglio, P.M. (2001) is responsible for epithelial morphogenesis. Nature A signaling adapter function for alpha6beta4 integrin 384: 173176. in the control of HGF-dependent invasive growth. Cell 107: 643654. Xiao, G.H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude, G.F. and Testa, J.R. (2001) Anti- Trusolino, L., Bertotti, A. and Comoglio, P.M. (2010) apoptotic signaling by hepatocyte growth factor/Met MET signalling: principles and functions in develop- via the phosphatidylinositol 3-kinase/Akt and mitogen- ment, organ regeneration and cancer. Nat Rev Mol Cell activated protein kinase pathways. Proc Natl Acad Sci Biol 11: 834848. USA 98: 247252. Trusolino, L. and Comoglio, P.M. (2002) Scatter- Yeh, C.Y., Shin, S.M., Yeh, H.H., Wu, T.J., Shin, J.W., factor and semaphorin receptors: cell signalling for Chang, T.Y. et al. (2011) Transcriptional activation of invasive growth. Nat Rev Cancer 2: 289300. the Axl and PDGFR-alpha by c-Met through a ras- and Src-independent mechanism in human bladder Tsao, M.S., Liu, N., Chen, J.R., Pappas, J., Ho, J., To, cancer. BMC Cancer 11: 139. C. et al. (1998) Differential expression of Met/hepa- tocyte growth factor receptor in subtypes of non-small Zhang, Y.W., Wang, L.M., Jove, R. and Vande Woude, cell lung cancers. Lung Cancer 20: 116. G.F. (2002) Requirement of Stat3 signaling for HGF/ SF-Met mediated tumorigenesis. Oncogene Tuck, A.B., Park, M., Sterns, E.E., Boag, A. and 21: 217226. Elliott, B.E. (1996) Coexpression of hepatocyte growth factor and receptor (Met) in human breast Zhu, H., Naujokas, M.A. and Park, M. (1994) carcinoma. Am J Pathol 148: 225232. Receptor chimeras indicate that the met tyrosine Visit SAGE journals online kinase mediates the motility and morphogenic http://tam.sagepub.com Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, responses of hepatocyte growth/scatter factor. J., Noda, T. et al. (1995) Placental defect and embry- Cell Growth Differ 5: 359366. onic lethality in mice lacking hepatocyte growth factor/ scatter factor. Nature 373: 702705. http://tam.sagepub.com S19 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

An overview of the c-MET signaling pathway:

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Abstract

Therapeutic Advances in Medical Oncology Review Shawna Leslie Organ and Ming-Sound Tsao Abstract: c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor, activates a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological conditions, it has also been found to be aberrantly acti- vated in human cancers via mutation, amplification or protein overexpression. This paper provides an overview of the c-MET signaling pathway, including its role in the development of cancers, and provides a rationale for targeting the pathway as a possible treatment option. Keywords: cancer, c-MET, hepatocyte growth factor (HGF), MET, signaling, receptor tyrosine kinase Receptor tyrosine kinases muscle and bone marrow, during both embryo- Receptor tyrosine kinases (RTKs) regulate many genesis and adulthood [Comoglio et al. 2008]. essential cellular processes in mammalian devel- opment, cell function and tissue homeostasis. The c-MET receptor is formed by proteolytic pro- However, although RTKs are important in cessing of a common precursor in the post-Golgi normal physiology, dysregulation of certain RTKs compartment into a single-pass, disulphide-linked has been implicated in the development and a/b heterodimer (Figure 1a.) [Trusolino and progression of many types of cancer [Krause and Comoglio, 2002]. The extracellular portion of Van Etten, 2005]. For example, expression of the c-MET is composed of three domain types. The c-MET RTK and its ligand, hepatocyte growth N-terminal 500 residues fold to form a large sema- factor (HGF), has been observed in tumor biop- phorin (Sema) domain, which encompasses the sies of most solid tumors and c-MET signal- whole a-subunit and part of the b-subunit. The ing has been documented in a wide range of Sema domain shares sequence homology with human malignancies [Peruzzi and Bottaro, 2006; domains found in the semaphorin and plexin fam- Birchmeier et al. 2003; Comoglio and Trusolino, ilies. The PSI domain (found in plexins, sema- 2002]. This paper provides an overview of the phorins and integrins) follows the Sema domain, c-MET signaling pathway, including its role in spans approximately 50 residues and includes the development of cancers, and provides a ratio- four disulphide bonds. This domain is connected nale for targeting the pathway as a possible treat- to the transmembrane helix via four immunoglob- ment option. ulinplexintranscription (IPT) domains, which are related to immunoglobulin-like domains and Hepatocyte growth factor and c-MET: are found in integrins, plexins and transcription structure and function factors. Intracellularly, the c-MET receptor con- The c-MET proto-oncogene is located on chro- tains a tyrosine kinase catalytic domain flanked by mosome 7q21-31. Its transcription is regulated distinctive juxtamembrane and carboxy-terminal by Ets (E-twenty six), Pax3 (paired box 3), AP2 sequences. (activator protein-2) and Tcf-4 (transcription factor 4) [Boon et al. 2002; Epstein et al. 1996; The ligand for c-MET was identified by two Gambarotta et al. 1996; Boccaccio et al. 1994], independent studies as both a motility factor and a scatter factor for hepatocytes, and this and it is expressed as multiple mRNA transcripts of 8, 7, 4.5, 3 and 1.5 kilobases [Park et al. 1986]. factor was later found to be the same molecule: The protein product of this gene is the c-MET HGF, also known as scatter factor (SF) [Weidner tyrosine kinase. This cell surface receptor is et al. 1991; Nakamura et al. 1989; Stoker et al. expressed in epithelial cells of many organs, 1987]. HGF acts as a pleiotropic factor and cyto- including the liver, pancreas, prostate, kidney, kine, promoting cell proliferation, survival, http://tam.sagepub.com S7 Therapeutic Advances in Medical Oncology 3 (1) (a) a-chain b-chain Sema domain ss PSI domain IPT domain Juxtamembrane Y1003 P domain Y1234 P Kinase domain Y1235 Y1349 Multifunctional docking site Y1356 P a-chain b-chain (b) R V K1 K2 K3 K4 Hairpin Kringle domains ss loop Figure 1. Domain structure of c-MET and hepatocyte growth factor (HGF). (a) The c-MET receptor is formed by proteolytic processing of a common precursor into a single-pass, disulphide-linked a/b heterodimer. The extra- cellular portion of c-MET is composed of three domain types. The N-terminal 500 residues fold to form a large semaphorin (Sema) domain, which encompasses the whole a-subunit and part of the b-subunit. The plex- insemaphorinintegrin (PSI) domain follows the Sema domain, spans approximately 50 residues and includes four disulphide bonds. This domain is connected to the transmembrane helix via four immunoglobu- linplexintranscription (IPT) domains, which are related to immunoglobulin-like domains. Intracellularly, the c-MET receptor contains a tyrosine kinase catalytic domain flanked by distinctive juxtamembrane and carboxy- terminal sequences. This portion of c-MET contains the catalytic tyrosines Y1234 and Y1235, which positively modulate enzyme activity, while the juxtamembrane tyrosine 1003 negatively regulates c-MET by recruiting the ubiquitin ligase casitas B-lineage lymphoma (c-CBL). The multifunctional docking site in the C-terminal tail con- tains tyrosines Y1349 and Y1356, which recruit several transducers and adaptors when c-MET is active. (b) The c-MET ligand, hepatocyte growth factor (HGF), is secreted by mesenchymal cells as a single-chain, biologically inert precursor and is converted into its bioactive form when extracellular proteases cleave the bond between Arg494 and Val495. The mature form of HGF consists of an a-and b-chain, which are held together by a disulphide bond. The a-chain contains an N-terminal hairpin loop followed by four kringle domains (80 amino acid double- looped structures formed by three internal disulphide bridges), K14. The b-chain is homologous to the serine proteases of the blood-clotting cascade, but lacks any proteolytic activity. Adapted from Comoglio et al. [2008]. motility, scattering, differentiation and morpho- et al. 1999], lung fibrosis [Watanabe et al. 2005] genesis [Basilico et al. 2008; Birchmeier et al. and progressive nephropathies [Liu and Yang, 2003; Trusolino and Comoglio, 2002]. In addi- 2006; Okada and Kalluri, 2005]. HGF is tion, HGF appears to play a protective role in secreted by mesenchymal cells as a single-chain, several diseases, including liver cirrhosis [Ueki biologically inert precursor and is converted into S8 http://tam.sagepub.com SL Organ and M-S Tsao its bioactive form when extracellular proteases 1995] and v-crk sarcoma virus CT10 oncogene cleave the bond between Arg494 and Val495. homolog (CRK) and CRK-like (CRKL) [Sakkab The mature form of HGF consists of an a- and et al. 2000; Garcia-Guzman et al. 1999], the effec- b-chain, which are held together by a disulphide tor molecules phosphatidylinositol 3-kinase bond. The a-chain contains an N-terminal hair- (PI3K), phospholipase Cg (PLCg) and v-src sar- pin loop followed by four kringle domains (80 coma (Schmidt-Ruppin A-2) viral oncogene amino acid double-looped structures formed by homolog (SRC) [Ponzetto et al. 1994], Src homol- three internal disulphide bridges). The b-chain ogy domain-containing 5’ inositol phosphatase is homologous to serine proteases of the blood- (SHIP-2) [Koch et al. 2005] and the transcription clotting cascade, but lacks proteolytic activity factor signal transducer and activator of transcrip- (Figure 1b). tion (STAT-3) [Zhang et al. 2002; Boccaccio et al. 1998] (Figure 2). In addition, unique to c-MET is Physiologically, c-MET is responsible for the its association with the adaptor protein GRB2- cell-scattering phenotype, as first demonstrated associated binding protein 1 (GAB1) [Weidner with MDCK cells treated with HGF [Zhu et al. et al. 1996], a multi-adaptor protein that, once 1994]. This process involves the disruption of bound to and phosphorylated by c-MET, creates cadherin-based cellcell contacts and subsequent binding sites for more downstream adaptors. cell motility, and is a key epithelial function in GAB1 can bind either directly to c-MET or indi- embryogenesis and wound repair [Corso et al. rectly, through GRB2. Additional tyrosines can 2005]. During embryogenesis, this motility func- also contribute to c-MET signaling. When Y1313 tion of c-MET is crucial for the long-range is phosphorylated, it binds and activates PI3K, migration of skeletal muscle progenitor cells. which probably promotes cell viability and motility Ablation of the MET or Hgf gene in mice results [Maulik et al. 2002a]. In addition, Y1365 regulates in the complete absence of all muscle groups cell morphogenesis when phosphorylated [Maulik derived from these cells [Bladt et al. 1995]. et al. 2002a]. During development, c-MET and HGF provide essential signals for survival and proliferation of The downstream response to c-MET activation hepatocytes and placental trophoblast cells; con- relies on stereotypical signaling modulators sequently, MET or Hgf knockout embryos show common to many RTKs. These pathways markedly reduced liver size. As well, altered pla- have been reviewed in detail [Trusolino et al. cental development in Hgf and MET knockout 2010], and are summarized in Figure 2. For mice is responsible for the death of these animals activation of the Mitogen activated protein in utero [Schmidt et al. 1995; Uehara et al. 1995]. kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral HGF/c-MET signaling oncogene homolog (RAS) guanine nucleotide The complex phenotype that results from c-MET exchanger Son of Sevenless (SOS) via binding signaling involves a number of molecular events, with SHC and GRB2 [Graziani et al. 1993], which have been described in detail in previous leading to the activation of RAS. This leads to reviews [Trusolino et al. 2010; Liu et al. 2008; the indirect activation of v-raf murine sarcoma Peruzzi and Bottaro, 2006; Birchmeier et al. viral oncogene homolog B1 (RAF) kinases, 2003; Maulik et al. 2002b]. HGF binding to c- which can subsequently activate the MAPK MET results in receptor homodimerization and effector kinase MEK and finally MAPK, phosphorylation of two tyrosine residues (Y1234 which can then translocate to the nucleus to and Y1235) located within the catalytic loop of activate transcription factors responsible for the tyrosine kinase domain [Rodrigues and Park, regulating a large number of genes. In the con- 1994]. Subsequently, tyrosines 1349 and 1356 in text of c-MET signaling, this results in pheno- the carboxy-terminal tail become phosphory- types such as cell proliferation, cell motility lated. These two tyrosines form a tandem SH2 and cell cycle progression [Paumelle et al. recognition motif unique to c-MET 2002; Fixman et al. 1996]. Src homology 2 1349 1356 (Y VHVX Y VNV) [Ponzetto et al. domain-containing phosphatase-2 (SHP2) can 1994]. When these tyrosines become phosphory- also link c-MET signaling to the MAPK cas- lated, they recruit signaling effectors that include cade, as sequestration of SHP2 to GAB1 is the adaptor proteins Growth factor receptor- responsible for extending the duration of bound protein 2 (GRB2) [Fixman et al. 1996], MAPK phosphorylation [Maroun et al. 2003; Src homology-2-containing (SHC) [Pelicci et al. Schaeer et al. 2000]. http://tam.sagepub.com S9 Therapeutic Advances in Medical Oncology 3 (1) HGF c-MET PTPs CBL Negative c-MET DAG PKC P P regulation PIP3 PP IP3 Ca PLCγ1 Src SHP2 Akt/PKB SOS Ras PI3K PP GRB2 SHC GRB2PP GAB1 SHC PLCγ1 FAK GAB1 STAT3 Raf PI3K SHP2 CRK CRK ERK/MAPK JNK Survival Gene expression changes Transformation Motility Proliferation Invasion Cell cycle progression Figure 2. c-MET signaling adaptors and mediators. When the tyrosines within the multifunctional docking site become phosphorylated they recruit signaling effectors, including the adaptor proteins growth factor receptor-bound protein 2 (GRB2), src homology 2 domain-containing (SHC), v-crk sarcoma virus CT10 oncogene homolog (CRK) and CRK-like (CRKL); the effector molecules phosphatidylinositol 3-kinase (PI3K), phospholipase Cg (PLCg) and SRC, the src homology 2 domain-containing 5’ inositol phosphatase SHIP-2, and the signal transducer and activator of transcription STAT3. In addition, unique to c-MET is its association with the adaptor protein GRB2-associated binding protein 1 (GAB1), a multi-adaptor protein that, once bound to and phosphorylated by c-MET, creates binding sites for more downstream adaptors. GAB1 can bind either directly to c-MET or indirectly, through GRB2. The downstream response to c-MET activation relies on stereotypical signaling modulators common to many receptor tyrosine kinases. For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. This leads to the indirect activation of v-raf murine sarcoma viral oncogene homolog B1 (RAF) kinases, which can subsequently activate MAPK effector kinase (MEK), and finally MAPK, which can then translocate to the nucleus to activate the transcription factors responsible for regulating a large number of genes, including those involved in cell proliferation, cell motility and cell cycle progression. SHP2 can also link c-MET signaling to the MAPK cascade, as sequestration of SHP2 to GAB1 is responsible for extending the duration of MAPK phosphorylation. The p85 subunit of PI3K can bind either directly to c-MET or indirectly through GAB1, which then signals through AKT/protein kinase B. This axis is primarily responsible for the cell survival response to c-MET signaling. Transformation downstream of the c-MET receptor is mediated by the phosphorylation of Janus kinase 1 (JNK), which occurs via binding to CRK. STAT3 has also been implicated in transformation. The direct binding of STAT3 to c-MET results in STAT3 phosphorylation, dimerization and its translocation to the nucleus. This has been shown to result in tubulogenesis and invasion. However, other reports have found that, although STAT3 is required for c-MET- mediated tumorigenesis, it has no effect on proliferation, invasion or branching morphogenesis. Cellular migration is also mediated downstream of c- MET by focal adhesion kinase (FAK), which is localized to cellular adhesion complexes. FAK is activated through phosphorylation by SRC family kinases, which have been shown to directly associate with c-MET. The c-METSRCFAK interaction leads to cell migration and the promotion of anchorage- independent growth. Negative regulation of the c-MET receptor is crucial for its tightly controlled activity. The Y1003 site, located in the juxtamembrane domain, is a negative regulatory site for c-MET signaling that acts by recruiting c-CBL. Regulation of c-MET signaling is also accomplished via its binding to various protein tyrosine phosphatases (PTPs). These PTPs modulate c-MET signaling by dephosphorylation of either the tyrosines in the c-MET kinase or the docking site. Finally, binding of PLCg to c-MET results in the activation of protein kinase C (PKC), which can then negatively regulate c-MET receptor phosphorylation and activity. Independently of PKC activation, an increase in intracellular calcium levels can also lead to negative c-MET regulation. Adapted from Trusolino et al. [2010] and Birchmeier et al. [2003]. DAG, diacylglycerol; HGF, hepatocyte growth factor; IP3, inositol triphos- phate; PIP3, phosphatidylinositol (3,4,5)-triphosphate. S10 http://tam.sagepub.com SL Organ and M-S Tsao The other major arm of c-MET signaling is the enhanced phosphatase 1 (dEP1) (or PTPrI) PI3K/Akt signaling axis. The p85 subunit of and leukocyte common antigen-related molecule PI3K can bind either directly to c-MET or indi- (LAR) (or PTPrF) [Machide et al. 2006; Palka rectly through GAB1, which then signals through et al. 2003], and the nonreceptor PTPs PTP1B AKT/protein kinase B. This axis is primarily and T-cell protein tyrosine phosphatase responsible for the cell survival response to (TCPTP) [Sangwan et al. 2008]. These PTPs c-MET signaling [Xiao et al. 2001]. modulate c-MET signaling by dephosphorylation Transformation downstream of the c-MET of either the tyrosines in the c-MET kinase receptor is mediated by the phosphorylation of domain (in the case of PTP1b and TCPTP) or Janus kinase 1 (JNK), which occurs via binding the docking tyrosines (in the case of dEP1). to CRK [Garcia-Guzman et al. 1999; Rodrigues Finally, binding of PLCg to c-MET results in et al. 1997]. STAT3 has also been implicated in the activation of protein kinase C (PKC), which transformation, although its proposed mecha- can then negatively regulate c-MET receptor nism is controversial. The direct binding of phosphorylation and activity [Gandino et al. STAT3 to c-MET results in STAT3 phosphory- 1994; Gandino et al. 1990]. Independently of lation, dimerization and its translocation to the PKC activation, an increase in intracellular cal- nucleus. This has been shown to result in tubu- cium levels can also lead to negative c-MET reg- logenesis [Boccaccio et al. 1998] and invasion ulation [Gandino et al. 1991]. [Syed et al. 2011]. However, other reports found that, although it is required for c-MET- Although the downstream response to c-MET is mediated tumorigenesis, it has no effect on pro- common to many RTKs, the potency, endurance liferation, invasion or branching morphogenesis and specificity of c-MET-triggered pathways is [Zhang et al. 2002]. Therefore, the role of secured by a network of upstream signaling co- STAT3 in c-MET signaling is probably context- receptors that physically associate with c-MET at and tissue-dependent. the cell surface (Figure 3) [Trusolino et al. 2010]. c-MET membrane partners can then amplify Cellular migration is also mediated downstream and/or diversify c-MET-dependent biochemical of c-MET by focal adhesion kinase (FAK), which inputs and translate them into meaningful (and is localized to cellular adhesion complexes. FAK specific) biological outcomes. For instance, the is activated through phosphorylation by SRC v6 splice variant of the hyaluronan receptor family kinases, which have been shown to associ- CD44 links c-MET signaling to the actin cyto- ate directly with c-MET [Ponzetto et al. 1994]. skeleton via GRB2 and the ezrin, radixin and The c-METSRCFAK interaction leads to cell moesin (ERM) family of proteins in order to migration and the promotion of anchorage-inde- recruit SOS, which then amplifies RAS-ERK sig- pendent growth [Hui et al. 2009; Rahimi et al. naling [Orian-Rousseau et al. 2007]. Recent work 1998]. In addition, SRC activation can positively has also shown that intercellular adhesion mole- feed back on c-MET activation [Organ et al. cule 1 (ICAM-1) can substitute for CD44v6 as a 2011; Hui et al. 2009]. Because of this, combi- co-receptor for c-MET in CD44v6 knockout natorial therapies involving both c-MET and mice, resulting in similar c-MET pathway activa- SRC inhibitors show promise in the treatment tion [Olaku et al. 2011]. As another example, c- of cancers dependent on either kinase [Sen MET binding to integrin a6b4 creates a supple- et al. 2011; Bertotti et al. 2010; Okamoto et al. mentary docking platform for binding of signal- 2010]. ing adaptors, leading to specific enhancement of PI3K, RAS and SRC activation [Trusolino et al. Negative regulation of the c-MET receptor is 2001; Bertotti et al. 2005]. In addition, the G- crucial for its tightly controlled activity, and can protein-coupled receptor (GPCR) agonists lyso- occur through a number of mechanisms. The phosphatidic acid (LPA), bradykinin, thrombin Y1003 site, located in the juxtamembrane and carbachol can induce c-MET phosphoryla- domain, is a negative regulatory site for c-MET tion [Fischer et al. 2004], although the functional signaling that acts by recruiting c-CBL (casitas consequences of these interactions are still B-lineage lymphoma) [Petrelli et al. 2002; unclear. Peschard et al. 2001]. Regulation of c-MET sig- naling is also accomplished via its binding to var- Crosstalk between c-MET and other RTKs has ious protein tyrosine phosphatases (PTPs), also been studied in great depth because of its including the receptor-type PTPs density potential importance in the development of http://tam.sagepub.com S11 actin Therapeutic Advances in Medical Oncology 3 (1) HGF HGF Ligand c-MET c-MET c-MET CD44/ICAM1 c-MET GPCR a6 b4 RTKs Agonist Integrin P PI3K SHP2 P P ERM P P P Src P SOS GRB2 SHC GRB2 SOS Amplification of Amplification of c-MET phosphorylation Ligand-independent RAS signaling RAS, Src, PI3K pathways and pathway activation transactivation of c-MET signaling Figure 3. c-MET transactivation. The potency and endurance of c-MET-triggered pathways is secured by a network of upstream signaling co-receptors that physically associate with c-MET at the cell surface. c-MET membrane partners can then amplify and/or diversify c-MET-dependent biochemical inputs and translate them into meaningful (and specific) biological outcomes. The v6 splice variant of the hyaluronan receptor CD44 links c-MET signaling to the actin cytoskeleton via the growth factor receptor-bound protein 2 (GRB2) and the ezrin, radixin, moesin (ERM) family of proteins in order to recruit son of sevenless (SOS), which then amplifies RAS- ERK signaling. Intercellular adhesion molecule 1 (ICAM-1) can substitute for CD44v6 as a co-receptor for c-MET in CD44v6 knockout mice, resulting in similar c-MET pathway activation. c-MET binding to integrin a6b4 creates a supplementary docking platform for the binding of signaling adaptors, leading to specific enhancement of phosphatidylinositol 3-kinase (PI3K), RAS and SRC activation. c- MET can also be activated by G-protein coupled receptors (GPCRs), although the functional outcome of this interaction is not well characterized. Crosstalk between c-MET and other receptor tyrosine kinases (RTKs) has also been studied in great depth because of its potential importance in the development of resistance to cancer therapeutics. Examples of these RTKs include the semaphorin receptors, the epidermal growth factor receptor (EGFR) family of receptors, the recepteur d’origine nantais (RON), platelet-derived growth factor receptor (PDGFR) and Axl; the list continues to grow. Adapted from Trusolino et al. [2010] and Corso et al. [2005] HGF, hepatocyte growth factor; SHC, src homolgy 2 domain-containing; SHP2, src homology 2 domain-containing phosphatase 2. resistance to cancer therapeutics [Lai et al. 2009]. c-MET interaction with the other EGFR family For instance, several members of the family of members ERBB2 and ERBB3 (for erythroblastic semaphorin receptors, including the plexins and leukemia viral oncogene homologs B2 and B3), neuropilins, can transactivate c-MET in the causing transactivation of both receptors absence of HGF when stimulated by their sema- [Bachleitner-Hofmann et al. 2008; Khoury et al. phorin ligands [Sierra et al. 2008; Hu et al. 2007; 2005]. Interaction of c-MET with the closely Conrotto et al. 2004]. c-MET has also been related RON (recepteur d’origine nantais) recep- shown by multiple studies to interact directly tor has also been shown to cause transphosphor- with the epidermal growth factor receptor ylation of the c-MET receptor in the absence of (EGFR), allowing activation of c-MET after HGF [Follenzi et al. 2000]. Interestingly, it was stimulation of cells with the EGFR ligands EGF recently shown that transactivation of RON by c- or transforming growth factor (TGF-a) [Jo et al. MET may be a feature of cancer cells that are 2000]. Stimulation of cells expressing both c- ‘addicted’ to c-MET signaling [Benvenuti et al. METand EGFR with EGF resulted in phosphor- 2011]. Recently, transactivation between c-Met ylation of c-MET, and stimulation with ligands and both platelet-derived growth factor receptor for both receptors resulted in synergistic activa- (PDGFR) and Axl was found to play a role in tion of downstream modulators, indicating bladder cancer [Yeh et al. 2011]. The list of cell mutual activation of these two pathways [Puri surface receptors that play a role in c-MET sig- and Salgia, 2008]. Evidence also exists for naling is growing constantly, and highlights the S12 http://tam.sagepub.com SL Organ and M-S Tsao importance of personally targeted cancer thera- suggesting that this genetic lesion can predispose pies, depending on the expression of these RTKs to the development of gastric carcinomas [Soman in specific patients. et al. 1991]. The c-MET receptor relies on its multitude of sig- Amplification of the c-MET gene, with conse- naling adaptors and cell surface co-receptors to quent protein overexpression and constitutive mediate biological responses unique to the recep- kinase activation, has been reported in a tor. Recent large-scale phosphoproteomic studies number of human primary tumors. These have provided even more insight into the intrica- include gastric and oesophageal carcinomas cies of the HGF/c-MET signaling axis [Organ [Miller et al. 2006; Hara et al. 1998; Kuniyasu et al. 2011; Hammond et al. 2010; Guo et al. et al. 1992; Houldsworth et al. 1990], medullo- 2008]. Although these studies identified the blastomas [Tong et al. 2004], and liver metastases highly conserved, core elements in c-MET signal- from colon carcinoma [Di Renzo et al. 1995c]. ing, they also identified tissue-specific differences, This last finding suggests that MET gene ampli- in addition to activation- compared with inhibi- fication can be acquired during the course of tion-specific differences, in downstream mediators tumor progression. Interestingly, recent research of c-MET. Although much work has been done has shown that non-small cell lung carcinomas since the discovery of the c-MET oncogene to with acquired resistance to EGFR inhibitors map out the details of c-MET signaling, this sug- tend to show amplifications in MET [Bean et al. gests that our understanding of the greater c-MET 2007; Engelman et al. 2007]. This suggests that network remains incomplete. combined treatment with EGFR and c-MET inhibitors could be necessary in a subset of HGF/c-MET signaling in cancer patients to circumvent the onset of resistance to As described above, c-MET signaling is an intri- these drugs. cate and highly regulated process. Mechanisms operating during tumor growth or cancer pro- The most convincing evidence that implicates gression have been identified that can result in c-MET in human cancers is provided by the acti- constitutive or prolonged activation of c-MET. vating mutations that were discovered in the Data collected from in vitro and in vivo tumor c-MET kinase domain in both sporadic and models suggest that these typically take place by inherited forms of human renal papillary carcino- means of three mechanisms: the occurrence of mas [Olivero et al. 1999; Schmidt et al. 1999]. specific genetic lesions, including translocations, Activating kinase domain mutations have subse- gene amplifications and activating mutations; by quently been identified in a small number of transcriptional upregulation of the c-MET pro- other cancers. Mutations have also been identi- tein in the absence of gene amplification; or via fied in the c-CBL binding site of the juxtamem- ligand-dependent autocrine or paracrine mecha- brane domain and in the HGF-binding region of nisms [Danilkovitch-Miagkova and Zbar, 2002]. the Sema domain [Forbes et al. 2008]. In hered- itary cancers, heterozygous mutations are usually c-MET was originally identified as an oncogene accompanied by trisomy of the whole chromo- in the 1980s [Cooper et al. 1984], isolated first some 7, suggesting that when only a single from a human osteosarcoma cell line treated with allele is mutated the mutation must be present the carcinogen N-methyl-N-nitro-N-nitrosogua- in multiple copies to produce the full trans- nidine. The c-MET identified in this cell line formed phenotype [Schmidt et al. 1997]. contained a chromosomal rearrangement that fused the tyrosine kinase domain of the c-MET Increased protein expression as a consequence of proto-oncogene to an upstream translocating transcriptional upregulation in the absence promoter region (TPR). This rearrangement of gene amplification is the most frequent cause caused constitutive dimerization and therefore of constitutive c-MET activation in human activation of the encoded protein [Park et al. tumors [Comoglio et al. 2008], and has been 1986]. Expression of TPR-MET in transgenic reported in an ever growing number of carcino- mice resulted in the development of multiple mas, including thyroid [Di Renzo et al. 1992; Di epithelial-derived tumors [Liang et al. 1996]. In Renzo et al. 1995b], colorectal [Hiscox et al. humans, the TPR-MET translocation has been 1997; Di Renzo et al. 1995a; Liu et al. 1992], found in both the precursor lesions of gastric can- ovarian [Di Renzo et al. 1994], pancreatic [Di cers and in the adjacent normal mucosa, Renzo et al. 1995b; Furukawa et al. 1995], lung http://tam.sagepub.com S13 Therapeutic Advances in Medical Oncology 3 (1) [Nakamura et al. 2008; Tsao et al. 1998] and continues to strongly suggest that amplification breast [Lengyel et al. 2005], to name a few. of the MET gene might be a genetic predictor of Hypoxia, caused by lack of oxygen diffusion to therapeutic responsiveness [Lutterbach et al. the centre of a growing tumor, is one mechanism 2007; Smolen et al. 2006]. that has been demonstrated to activate c-MET transcription in vitro and in vivo [Pennacchietti ‘Oncogene expedience’ is a tumor-specific term et al. 2003]. Hypoxia activates the c-MET pro- that describes the scattering, invasion and sur- moter, via the transcription factor hypoxia induc- vival of cancer cells associated with metastatic ible factor 1a (HIF1a), which itself is regulated spreading [Comoglio et al. 2008]. In contrast to by the concentration of intracellular oxygen oncogene addiction, the inappropriate activation [Kitajima et al. 2008]. of c-MET resulting in oncogene expedience is the consequence rather than the cause of the trans- Although c-MET activation via a ligand-depen- formed phenotype. Thus, activation of c-MET is dent autocrine or paracrine loop will be fully dis- a secondary event in various types of tumor, exac- cussed elsewhere in this supplement, we will erbating the malignant properties of already touch on it briefly here. HGF is expressed ubiq- transformed cells. In these cases, aberrant c- uitously within the body and has been found to MET activation occurs through a number of pos- be frequently overexpressed in the reactive sible routes; these include transcriptional upregu- stroma of primary tumors [Matsumoto and lation by other oncogenes [Abounader et al. Nakamura, 2006]. This supports the formation 2004; Ivan et al. 1997], environmental conditions of paracrine positive feedback loops, which in such as hypoxia [Pennacchietti et al. 2003] and turn can support the dissemination of cancer agents secreted by reactive stroma such as inflam- cells to distant locations. The autocrine stimula- matory cytokines, proangiogenic factors and tion of c-MET has also been identified in cancer HGF itself [Bhowmick et al. 2004; Boccaccio cells [Rahimi et al. 1996; Rong and Vande et al. 1994]. Woude, 1994], and appears to be indicative of increased aggressiveness of tumors along with As MET is a necessary oncogene for a number of poor prognostic signs in cancer patients [Navab neoplasms, targeted therapies against c-MET et al. 2009; Vadnais et al. 2002; Tuck et al. 1996]. could be effective as a front-line intervention to treat a limited subset of c-MET-addicted c-MET as a target for therapeutic inhibition tumors and subsequent c-MET-addicted metas- Although the development of c-MET inhibitors tases [Comoglio et al. 2008]. In addition, as MET will be discussed elsewhere in this supplement, also acts as an adjuvant prometastatic gene here we consider the dual role c-MET plays for many neoplasms, targeted therapies against in both the development and progression of c-MET could also be used as a secondary cancers, and how each could be targeted by approach to hamper the progression of a much c-MET inhibitors. wider spectrum of advanced cancers that rely on c-MET activation for metastatic spreading. Some tumors appear to be dependent on (or ‘addicted’ to) sustained c-MET activity for their Summary and conclusions growth and survival, and this is often associated The HGF/c-MET pathway comprises a complex with MET gene amplification. This phenomenon and unique signaling network and plays a pivotal is known as ‘oncogene addiction’ and applies to all role in both normal development and cancer pro- settings where cancer cells appear to be dependent gression. c-MET controls multiple biological on a single overactive oncogene for their prolifer- functions, including proliferation, survival, motil- ation and survival [Sharma et al. 2007; Sharma ity and invasion, which, when dysregulated by and Settleman, 2007]. Oncogene addiction was aberrant c-MET activation, can lead to both identified after studies using EGFR tyrosine tumor growth and metastatic progression of kinase inhibitors demonstrated that these inhibi- cancer cells. Consequently, c-MET is a versatile tors were efficacious only in a small subset of candidate for targeted therapeutic intervention. tumors which exhibited genetic alterations of the receptor itself [Sharma et al. 2007]. Although this Acknowledgement c-MET-addicted phenotype has only recently been Matthew Joynson, a medical writer, assisted with (yet consistently) described in cultured cells from the styling of this manuscript. The authors wrote gastric and non-small cell lung carcinomas, it and revised the main draft of the article. S14 http://tam.sagepub.com SL Organ and M-S Tsao Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A. Funding and Birchmeier, C. (1995) Essential role for the c-met This study was supported by the Canadian receptor in the migration of myogenic precursor cells Institutes of Health Research (grant number into the limb bud. Nature 376: 768771. MOP-64345) and in part by the Ontario Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Ministry of Health and Long Term Care. SLO Michieli, P., Battistini, C. et al. (1998) Induction of is supported by the CIHR Banting and Best epithelial tubules by growth factor HGF depends on Doctoral Research Award. MST is the M. the STAT pathway. Nature 391: 285288. Qasim Choksi Chair in Lung Cancer Boccaccio, C., Gaudino, G., Gambarotta, G., Galimi, Translational Research. Editorial assistance was F. and Comoglio, P.M. (1994) Hepatocyte growth funded by Daiichi Sankyo Europe GmbH. factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. J Biol Chem 269: 1284612851. Conflict of interest statement Shawna L. Organ declares no conflict of interest. Boon, E.M., van der Neut, R., van de Wetering, M., Dr Ming-Sound Tsao has received honoraria Clevers, H. and Pals, S.T. (2002) Wnt signaling reg- from Daiichi Sankyo Europe GmbH for speaking ulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res 62: 51265128. at scientific symposia. Comoglio, P.M., Giordano, S. and Trusolino, L. (2008) Drug development of MET inhibitors: target- ing oncogene addiction and expedience. Nat Rev Drug References Discov 7: 504516. Abounader, R., Reznik, T., Colantuoni, C., Martinez- Murillo, F., Rosen, E.M. and Laterra, J. (2004) Comoglio, P.M. and Trusolino, L. (2002) Invasive Regulation of c-Met-dependent gene expression by growth: from development to metastasis. J Clin Invest PTEN. Oncogene 23: 91739182. 109: 857862. Bachleitner-Hofmann, T., Sun, M.Y., Chen, C.T., Conrotto, P., Corso, S., Gamberini, S., Comoglio, Tang, L., Song, L., Zeng, Z. et al. (2008) HER kinase P.M. and Giordano, S. (2004) Interplay between activation confers resistance to MET tyrosine kinase scatter factor receptors and B plexins controls invasive inhibition in MET oncogene-addicted gastric cancer growth. Oncogene 23: 51315137. cells. Mol Cancer Ther 7: 34993508. Cooper, C.S., Park, M., Blair, D.G., Tainsky, M.A., Basilico, C., Arnesano, A., Galluzzo, M., Comoglio, Huebner, K., Croce, C.M. et al. (1984) Molecular P.M. and Michieli, P. (2008) A high affinity hepatocyte cloning of a new transforming gene from a chemically growth factor-binding site in the immunoglobulin-like transformed human cell line. Nature 311: 2933. region of Met. J Biol Chem 283: 2126721277. Corso, S., Comoglio, P.M. and Giordano, S. (2005) Bean, J., Brennan, C., Shih, J.Y., Riely, G., Viale, A., Cancer therapy: can the challenge be MET? Trends Wang, L. et al. (2007) MET amplification occurs with Mol Med 11: 284292. or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erloti- Danilkovitch-Miagkova, A. and Zbar, B. (2002) nib. Proc Natl Acad Sci USA 104: 2093220937. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 109: 863867. Benvenuti, S., Lazzari, L., Arnesano, A., Li Chiavi, G., Gentile, A. and Comoglio, P.M. (2011) Ron kinase Di Renzo, M.F., Olivero, M., Ferro, S., Prat, M., transphosphorylation sustains MET oncogene addic- Bongarzone, I., Pilotti, S. et al. (1992) Overexpression tion. Cancer Res 71: 19451955. of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7: 25492553. Bertotti, A., Bracco, C., Girolami, F., Torti, D., Gastaldi, S., Galimi, F. et al. (2010) Inhibition of Src Di Renzo, M.F., Olivero, M., Giacomini, A., Porte, impairs the growth of met-addicted gastric tumors. H., Chastre, E., Mirossay, L. et al. (1995a) Clin Cancer Res 16: 39333943. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal Bertotti, A., Comoglio, P.M. and Trusolino, L. (2005) cancer. Clinical Cancer Res 1: 147154. Beta4 integrin is a transforming molecule that unleashes Met tyrosine kinase tumorigenesis. Cancer Di Renzo, M.F., Olivero, M., Katsaros, D., Crepaldi, Res 65: 1067410679. T., Gaglia, P., Zola, P. et al. (1994) Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer Bhowmick, N.A., Neilson, E.G. and Moses, H.L. 58: 658662. (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432: 332337. Di Renzo, M.F., Olivero, M., Serini, G., Orlandi, F., Pilotti, S., Belfiore, A. et al. (1995b) Overexpression of Birchmeier, C., Birchmeier, W., Gherardi, E. and the c-MET/HGF receptor in human thyroid carcino- Vande Woude, G.F. (2003) Met, metastasis, mas derived from the follicular epithelium. J Endocrinol motility and more. Nat Rev Mol Cell Biol Invest 18: 134139. 4: 915925. http://tam.sagepub.com S15 Therapeutic Advances in Medical Oncology 3 (1) Di Renzo, M.F., Poulsom, R., Olivero, M., Comoglio, Graziani, A., Gramaglia, D., dalla Zonca, P. and P.M. and Lemoine, N.R. (1995c) Expression of the Comoglio, P.M. (1993) Hepatocyte growth Met/hepatocyte growth factor receptor in human factor/scatter factor stimulates the Ras-guanine pancreatic cancer. Cancer Res 55: 11291138. nucleotide exchanger. J Biol Chem 268: 91659168. Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O. et al. (2007) MET amplifi- Guo, A., Villen, J., Kornhauser, J., Lee, K.A., Stokes, cation leads to gefitinib resistance in lung cancer by M.P., Rikova, K. et al. (2008) Signaling networks activating ERBB3 signaling. Science 316: 10391043. assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105: 692697. Epstein, J.A., Shapiro, D.N., Cheng, J., Lam, P.Y. and Maas, R.L. (1996) Pax3 modulates expression of the Hammond, D.E., Hyde, R., Kratchmarova, I., c-Met receptor during limb muscle development. Proc Beynon, R.J., Blagoev, B. and Clague, M.J. (2010) Natl Acad Sci USA 93: 42134218. Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks. J Proteome Res Fischer, O.M., Giordano, S., Comoglio, P.M. and 9: 27342742. Ullrich, A. (2004) Reactive oxygen species mediate Met receptor transactivation by G protein-coupled Hara, T., Ooi, A., Kobayashi, M., Mai, M., receptors and the epidermal growth factor receptor in Yanagihara, K. and Nakanishi, I. (1998) Amplification human carcinoma cells. J Biol Chem of c-myc, K-sam, and c-met in gastric cancers: detec- 279: 2897028978. tion by fluorescence in situ hybridization. Lab Invest 78: 11431153. Fixman, E.D., Fournier, T.M., Kamikura, D.M., Naujokas, M.A. and Park, M. (1996) Pathways Hiscox, S.E., Hallett, M.B., Puntis, M.C., Nakamura, downstream of Shc and Grb2 are required for cell T. and Jiang, W.G. (1997) Expression of the HGF/SF transformation by the tpr-Met oncoprotein. J Biol receptor, c-met, and its ligand in human colorectal Chem 271: 1311613122. cancers. Cancer Invest 15: 513521. Follenzi, A., Bakovic, S., Gual, P., Stella, M.C., Houldsworth, J., Cordon-Cardo, C., Ladanyi, M., Longati, P. and Comoglio, P.M. (2000) Cross-talk Kelsen, D.P. and Chaganti, R.S. (1990) Gene ampli- between the proto-oncogenes Met and Ron. Oncogene fication in gastric and esophageal adenocarcinomas. 19: 30413049. Cancer Res 50: 64176422. Forbes, S.A., Bhamra, G., Bamford, S., Dawson, E., Hu, B., Guo, P., Bar-Joseph, I., Imanishi, Y., Jarzynka, Kok, C., Clements, J. et al. (2008) The Catalogue of M.J., Bogler, O. et al. (2007) Neuropilin-1 promotes Somatic Mutations in Cancer (COSMIC). Curr human glioma progression through potentiating the Protoc Hum Genet Chapter 10, Unit 10.11. activity of the HGF/SF autocrine pathway. Oncogene 26: 55775586. Furukawa, T., Duguid, W.P., Kobari, M., Matsuno, S. and Tsao, M.S. (1995) Hepatocyte growth factor and Hui, A.Y., Meens, J.A., Schick, C., Organ, S.L., Qiao, Met receptor expression in human pancreatic carci- H., Tremblay, E.A. et al. (2009) Src and FAK mediate nogenesis. Am J Pathol 147: 889895. cell-matrix adhesion-dependent activation of Met during transformation of breast epithelial cells. J Cell Gambarotta, G., Boccaccio, C., Giordano, S., Ando, Biochem 107: 11681181. M., Stella, M.C. and Comoglio, P.M. (1996) Ets up- regulates MET transcription. Oncogene Ivan, M., Bond, J.A., Prat, M., Comoglio, P.M. and 13: 19111917. Wynford-Thomas, D. (1997) Activated ras and ret oncogenes induce over-expression of c-met (hepato- Gandino, L., Di Renzo, M.F., Giordano, S., cyte growth factor receptor) in human thyroid epithe- Bussolino, F. and Comoglio, P.M. (1990) Protein lial cells. Oncogene 14: 24172423. kinase-c activation inhibits tyrosine phosphorylation of the c-met protein. Oncogene 5: 721725. Jo, M., Stolz, D.B., Esplen, J.E., Dorko, K., Michalopoulos, G.K. and Strom, S.C. (2000) Gandino, L., Longati, P., Medico, E., Prat, M. and Cross-talk between epidermal growth factor receptor Comoglio, P.M. (1994) Phosphorylation of serine 985 and c-Met signal pathways in transformed cells. J Biol negatively regulates the hepatocyte growth factor Chem 275: 88068811. receptor kinase. J Biol Chem 269: 18151820. Khoury, H., Naujokas, M.A., Zuo, D., Sangwan, V., Gandino, L., Munaron, L., Naldini, L., Ferracini, R., Frigault, M.M., Petkiewicz, S. et al. (2005) HGF Magni, M. and Comoglio, P.M. (1991) Intracellular converts ErbB2/Neu epithelial morphogenesis to cell calcium regulates the tyrosine kinase receptor encoded invasion. Mol Biol Cell 16: 550561. by the MET oncogene. J Biol Chem 266: 1609816104. Kitajima, Y., Ide, T., Ohtsuka, T. and Miyazaki, K. (2008) Induction of hepatocyte growth factor activator Garcia-Guzman, M., Dolfi, F., Zeh, K. and Vuori, K. gene expression under hypoxia activates the hepatocyte (1999) Met-induced JNK activation is mediated by the growth factor/c-Met system via hypoxia inducible adapter protein Crk and correlates with the Gab1 - Crk factor-1 in pancreatic cancer. Cancer Science signaling complex formation. Oncogene 99: 13411347. 18: 77757786. S16 http://tam.sagepub.com SL Organ and M-S Tsao Koch, A., Mancini, A., El Bounkari, O. and Tamura, tumor-stromal interactions. Int J Cancer T. (2005) The SH2-domain-containing inositol 5- 119: 477483. phosphatase (SHIP)-2 binds to c-Met directly via Maulik, G., Madhiwala, P., Brooks, S., Ma, P.C., tyrosine residue 1356 and involves hepatocyte growth Kijima, T., Tibaldi, E.V. et al. (2002a) Activated c-Met factor (HGF)-induced lamellipodium formation, cell signals through PI3K with dramatic effects on cyto- scattering and cell spreading. Oncogene skeletal functions in small cell lung cancer. J Cell Mol 24: 34363447. Med 6: 539553. Krause, D.S. and Van Etten, R.A. (2005) Tyrosine Maulik, G., Shrikhande, A., Kijima, T., Ma, P.C., kinases as targets for cancer therapy. N Engl J Med Morrison, P.T. and Salgia, R. (2002b) Role of the 353: 172187. hepatocyte growth factor receptor, c-Met, in onco- Kuniyasu, H., Yasui, W., Kitadai, Y., Yokozaki, H., Ito, genesis and potential for therapeutic inhibition. H. and Tahara, E. (1992) Frequent amplification of Cytokine Growth Factor Rev 13: 4159. the c-met gene in scirrhous type stomach cancer. Miller, C.T., Lin, L., Casper, A.M., Lim, J., Thomas, Biochem Biophys Res Commun 189: 227232. D.G., Orringer, M.B. et al. (2006) Genomic amplifi- Lai, A.Z., Abella, J.V. and Park, M. (2009) Crosstalk cation of MET with boundaries within fragile site in Met receptor oncogenesis. Trends Cell Biol FRA7G and upregulation of MET pathways in 19: 542551. esophageal adenocarcinoma. Oncogene 25: 409418. Lengyel, E., Prechtel, D., Resau, J.H., Gauger, K., Nakamura, T., Nishizawa, T., Hagiya, M., Seki, T., Welk, A., Lindemann, K. et al. (2005) C-Met overex- Shimonishi, M., Sugimura, A. et al. (1989) Molecular pression in node-positive breast cancer identifies cloning and expression of human hepatocyte growth patients with poor clinical outcome independent of factor. Nature 342: 440443. Her2/neu. Int J Cancer 113: 678682. Nakamura, Y., Matsubara, D., Goto, A., Ota, S., Liang, T.J., Reid, A.E., Xavier, R., Cardiff, R.D. and Sachiko, O., Ishikawa, S. et al. (2008) Constitutive Wang, T.C. (1996) Transgenic expression of tpr-met activation of c-Met is correlated with c-Met overex- oncogene leads to development of mammary hyper- pression and dependent on cell-matrix adhesion in plasia and tumors. J Clin Invest 97: 28722877. lung adenocarcinoma cell lines. Cancer Sci 99: 1422. Liu, C., Park, M. and Tsao, M.S. (1992) Navab, R., Liu, J., Seiden-Long, I., Shih, W., Li, M., Overexpression of c-met proto-oncogene but not epi- Bandarchi, B. et al. (2009) Co-overexpression of Met dermal growth factor receptor or c-erbB-2 in primary and hepatocyte growth factor promotes systemic human colorectal carcinomas. Oncogene 7: 181185. metastasis in NCI-H460 non-small cell lung carci- noma cells. Neoplasia 11: 12921300. Liu, X., Yao, W., Newton, R.C. and Scherle, P.A. (2008) Targeting the c-MET signaling pathway for Okada, H. and Kalluri, R. (2005) Cellular and cancer therapy. Expert Opin Investig Drugs molecular pathways that lead to progression and 17: 9971011. regression of renal fibrogenesis. Curr Mol Med 5: 467474. Liu, Y. and Yang, J. (2006) Hepatocyte growth factor: new arsenal in the fights against renal fibrosis? Kidney Okamoto, W., Okamoto, I., Yoshida, T., Okamoto, K., Int 70: 238240. Takezawa, K., Hatashita, E. et al. (2010) Identification of c-Src as a potential therapeutic target for gas- Lutterbach, B., Zeng, Q., Davis, L.J., Hatch, H., tric cancer and of MET activation as a cause of resis- Hang, G., Kohl, N.E. et al. (2007) Lung cancer cell tance to c-Src inhibition. Mol Cancer Ther lines harboring MET gene amplification are dependent 9: 11881197. on Met for growth and survival. Cancer Res 67: 20812088. Olaku, V., Matzke, A., Mitchell, C., Hasenauer, S., Sakkaravarthi, A., Pace, G. et al. (2011) c-Met recruits Machide, M., Hashigasako, A., Matsumoto, K. and ICAM-1 as a co-receptor to compensate for the loss of Nakamura, T. (2006) Contact inhibition of hepatocyte CD44 in the Cd44 null mice. Mol Biol Cell growth regulated by functional association of the 22: 27772786. c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. J Biol Chem Olivero, M., Valente, G., Bardelli, A., Longati, P., 281: 87658772. Ferrero, N., Cracco, C. et al. (1999) Novel mutation in the ATP-binding site of the MET oncogene tyrosine Maroun, C.R., Naujokas, M.A. and Park, M. (2003) kinase in a HPRCC family. Int J Cancer 82: 640643. Membrane targeting of Grb2-associated binder-1 (Gab1) scaffolding protein through Src myristoylation Organ, S.L., Tong, J., Taylor, P., St-Germain, J.R., sequence substitutes for Gab1 pleckstrin homology Navab, R., Moran, M.F. et al. (2011) Quantitative domain and switches an epidermal growth factor phospho-proteomic profiling of hepatocyte growth response to an invasive morphogenic program. factor (HGF)-MET signaling in colorectal cancer. Mol Biol Cell 14: 16911708. J Proteome Res 10: 32003211. Matsumoto, K. and Nakamura, T. (2006) Hepatocyte Orian-Rousseau, V., Morrison, H., Matzke, A., growth factor and the Met system as a mediator of Kastilan, T., Pace, G., Herrlich, P. et al. (2007) http://tam.sagepub.com S17 Therapeutic Advances in Medical Oncology 3 (1) Hepatocyte growth factor-induced Ras activation and oncogenic potential of the Met receptor tyrosine requires ERM proteins linked to both CD44v6 and kinase. Oncogene 9: 20192027. F-actin. Mol Biol Cell 18: 7683. Rodrigues, G.A., Park, M. and Schlessinger, J. (1997) Activation of the JNK pathway is essential for trans- Palka, H.L., Park, M. and Tonks, N.K. (2003) formation by the Met oncogene. EMBO J Hepatocyte growth factor receptor tyrosine kinase met 16: 26342645. is a substrate of the receptor protein-tyrosine phos- phatase DEP-1. J Biol Chem 278: 57285735. Rong, S. and Vande Woude, G.F. (1994) Autocrine mechanism for met proto-oncogene tumorigenicity. Park, M., Dean, M., Cooper, C.S., Schmidt, M., Cold Spring Harbor Symp Quant Biol 59: 629636. O’Brien, S.J., Blair, D.G. et al. (1986) Mechanism of met oncogene activation. Cell 45: 895904. Sakkab, D., Lewitzky, M., Posern, G., Schaeper, U., Sachs, M., Birchmeier, W. et al. (2000) Signaling of Paumelle, R., Tulasne, D., Kherrouche, Z., Plaza, S., hepatocyte growth factor/scatter factor (HGF) to the Leroy, C., Reveneau, S. et al. (2002) Hepatocyte small GTPase Rap1 via the large docking protein Gab1 growth factor/scatter factor activates the ETS1 tran- and the adapter protein CRKL. J Biol Chem scription factor by a RAS-RAF-MEK-ERK signaling 275: 1077210778. pathway. Oncogene 21: 23092319. Sangwan, V., Paliouras, G.N., Abella, J.V., Dube, N., Pelicci, G., Giordano, S., Zhen, Z., Salcini, A.E., Monast, A., Tremblay, M.L. et al. (2008) Regulation Lanfrancone, L., Bardelli, A. et al. (1995) The moto- of the Met receptor-tyrosine kinase by the protein- genic and mitogenic responses to HGF are amplified tyrosine phosphatase 1B and T-cell phosphatase. J Biol by the Shc adaptor protein. Oncogene 10: 16311638. Chem 283: 3437434383. Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., M., Giordano, S. and Comoglio, P.M. (2003) Hypoxia Kempkes, B. and Birchmeier, W. (2000) Coupling of promotes invasive growth by transcriptional activation Gab1 to c-Met, Grb2, and Shp2 mediates biological of the met protooncogene. Cancer Cell 3: 347361. responses. J Cell Biol 149: 14191432. Peruzzi, B. and Bottaro, D.P. (2006) Targeting the c- Schmidt, C., Bladt, F., Goedecke, S., Brinkmann, V., Met signaling pathway in cancer. Clin Cancer Res Zschiesche, W., Sharpe, M. et al. (1995) Scatter factor/ 12: 36573660. hepatocyte growth factor is essential for liver develop- ment. Nature 373: 699702. Peschard, P., Fournier, T.M., Lamorte, L., Naujokas, M.A., Band, H., Langdon, W.Y. et al. (2001) Mutation Schmidt, L., Duh, F.M., Chen, F., Kishida, T., Glenn, of the c-Cbl TKB domain binding site on the Met G., Choyke, P. et al. (1997) Germline and somatic receptor tyrosine kinase converts it into a transforming mutations in the tyrosine kinase domain of the MET protein. Mol Cell 8: 9951004. proto-oncogene in papillary renal carcinomas. Nat Genet 16: 6873. Petrelli, A., Gilestro, G.F., Lanzardo, S., Comoglio, P.M., Migone, N. and Giordano, S. (2002) The Schmidt, L., Junker, K., Nakaigawa, N., Kinjerski, T., endophilin-CIN85-Cbl complex mediates ligand- Weirich, G., Miller, M. et al. (1999) Novel mutations dependent downregulation of c-Met. Nature of the MET proto-oncogene in papillary renal carci- 416: 187190. nomas. Oncogene 18: 23432350. Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Sen, B., Peng, S., Saigal, B., Williams, M.D. and Zonca, P., Giordano, S. et al. (1994) A multifunctional Johnson, F.M. (2011) Distinct interactions between c- docking site mediates signaling and transformation by Src and c-Met in mediating resistance to c-Src inhi- the hepatocyte growth factor/scatter factor receptor bition in head and neck cancer. Clin Cancer Res family. Cell 77: 261271. 17: 514524. Puri, N. and Salgia, R. (2008) Synergism of EGFR Sharma, S.V., Bell, D.W., Settleman, J. and Haber, and c-Met pathways, cross-talk and inhibition, in non- D.A. (2007) Epidermal growth factor receptor muta- small cell lung cancer. J Carcinog 7: 9. tions in lung cancer. Nat Rev Cancer 7: 169181. Rahimi, N., Hung, W., Tremblay, E., Saulnier, R. and Sharma, S.V. and Settleman, J. (2007) Oncogene Elliott, B. (1998) c-Src kinase activity is required for addiction: setting the stage for molecularly targeted hepatocyte growth factor-induced motility and cancer therapy. Genes Dev 21: 32143231. anchorage-independent growth of mammary carci- Sierra, J.R., Corso, S., Caione, L., Cepero, V., noma cells. J Biol Chem 273: 3371433721. Conrotto, P., Cignetti, A. et al. (2008) Tumor angio- Rahimi, N., Tremblay, E., McAdam, L., Park, M., genesis and progression are enhanced by Sema4D Schwall, R. and Elliott, B. (1996) Identification produced by tumor-associated macrophages. J Exp of a hepatocyte growth factor autocrine loop in a Med 205: 16731685. murine mammary carcinoma. Cell Growth Differ Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., 7: 263270. Barmettler, A., Archibald, H. et al. (2006) Rodrigues, G.A. and Park, M. (1994) Amplification of MET may identify a subset of cancers Autophosphorylation modulates the kinase activity with extreme sensitivity to the selective tyrosine kinase S18 http://tam.sagepub.com SL Organ and M-S Tsao inhibitor PHA-665752. Proc Natl Acad Sci USA Ueki, T., Kaneda, Y., Tsutsui, H., Nakanishi, K., 103: 23162321. Sawa, Y., Morishita, R. et al. (1999) Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Soman, N.R., Correa, P., Ruiz, B.A. and Wogan, G.N. Med 5: 226230. (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and Vadnais, J., Nault, G., Daher, Z., Amraei, M., Dodier, precursor lesions. Proc Natl Acad Sci USA Y., Nabi, I.R. et al. (2002) Autocrine activation of the 88: 48924896. hepatocyte growth factor receptor/met tyrosine kinase induces tumor cell motility by regulating pseudopodial Stoker, M., Gherardi, E., Perryman, M. and Gray, J. protrusion. J Biol Chem 277: 4834248350. (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327: 239242. Watanabe, M., Ebina, M., Orson, F.M., Nakamura, A., Kubota, K., Koinuma, D. et al. (2005) Hepatocyte Syed, Z.A., Yin, W., Hughes, K., Gill, J.N., Shi, R. and growth factor gene transfer to alveolar septa for effec- Clifford, J.L. (2011) HGF/c-met/Stat3 signaling tive suppression of lung fibrosis. Mol Ther 12: 5867. during skin tumor cell invasion: indications for a pos- itive feedback loop. BMC Cancer 11: 180. Weidner, K.M., Arakaki, N., Hartmann, G., Vandekerckhove, J., Weingart, S., Rieder, H. et al. Tong, C.Y., Hui, A.B., Yin, X.L., Pang, J.C., Zhu, (1991) Evidence for the identity of human scatter X.L., Poon, W.S. et al. (2004) Detection of oncogene factor and human hepatocyte growth factor. Proc Natl amplifications in medulloblastomas by comparative Acad Sci USA 88: 70017005. genomic hybridization and array-based comparative genomic hybridization. J Neurosurg 100(2 Suppl Weidner, K.M., Di Cesare, S., Sachs, M., Brinkmann, Pediatrics): 187193. V., Behrens, J. and Birchmeier, W. (1996) Interaction between Gab1 and the c-Met receptor tyrosine kinase Trusolino, L., Bertotti, A. and Comoglio, P.M. (2001) is responsible for epithelial morphogenesis. Nature A signaling adapter function for alpha6beta4 integrin 384: 173176. in the control of HGF-dependent invasive growth. Cell 107: 643654. Xiao, G.H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude, G.F. and Testa, J.R. (2001) Anti- Trusolino, L., Bertotti, A. and Comoglio, P.M. (2010) apoptotic signaling by hepatocyte growth factor/Met MET signalling: principles and functions in develop- via the phosphatidylinositol 3-kinase/Akt and mitogen- ment, organ regeneration and cancer. Nat Rev Mol Cell activated protein kinase pathways. Proc Natl Acad Sci Biol 11: 834848. USA 98: 247252. Trusolino, L. and Comoglio, P.M. (2002) Scatter- Yeh, C.Y., Shin, S.M., Yeh, H.H., Wu, T.J., Shin, J.W., factor and semaphorin receptors: cell signalling for Chang, T.Y. et al. (2011) Transcriptional activation of invasive growth. Nat Rev Cancer 2: 289300. the Axl and PDGFR-alpha by c-Met through a ras- and Src-independent mechanism in human bladder Tsao, M.S., Liu, N., Chen, J.R., Pappas, J., Ho, J., To, cancer. BMC Cancer 11: 139. C. et al. (1998) Differential expression of Met/hepa- tocyte growth factor receptor in subtypes of non-small Zhang, Y.W., Wang, L.M., Jove, R. and Vande Woude, cell lung cancers. Lung Cancer 20: 116. G.F. (2002) Requirement of Stat3 signaling for HGF/ SF-Met mediated tumorigenesis. Oncogene Tuck, A.B., Park, M., Sterns, E.E., Boag, A. and 21: 217226. Elliott, B.E. (1996) Coexpression of hepatocyte growth factor and receptor (Met) in human breast Zhu, H., Naujokas, M.A. and Park, M. (1994) carcinoma. Am J Pathol 148: 225232. Receptor chimeras indicate that the met tyrosine Visit SAGE journals online kinase mediates the motility and morphogenic http://tam.sagepub.com Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, responses of hepatocyte growth/scatter factor. J., Noda, T. et al. (1995) Placental defect and embry- Cell Growth Differ 5: 359366. onic lethality in mice lacking hepatocyte growth factor/ scatter factor. Nature 373: 702705. http://tam.sagepub.com S19

Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Nov 1, 2011

Keywords: cancer; c-MET; hepatocyte growth factor (HGF); MET; signaling; receptor tyrosine kinase

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