|Met proto-oncogene (hepatocyte growth factor receptor)|
Crystallographic structure of MET. PDB rendering based on 1r0p.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR). The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.
MET proto-oncogene (GeneID: 4233) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7. MET is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.
MET is a receptor tyrosine kinase (RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at a furin site to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by a disulfide bridge.
- Region of homology to semaphorins (Sema domain), which includes the full α-chain and the N-terminal part of the β-chain
- Cysteine-rich MET-related sequence (MRS domain)
- Glycine-proline-rich repeats (G-P repeats)
- Four immunoglobulin-like structures (Ig domains), a typical protein-protein interaction region.
A Juxtamembrane segment that contains:
- a serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation
- a tyrosine (Tyr 1003), which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL
- Tyrosine kinase domain, which mediates MET biological activity. Following MET activation, transphosphorylation occurs on Tyr 1234 and Tyr 1235
- C-terminal region contains two crucial tyrosines (Tyr 1349 and Tyr 1356), which are inserted into the multisubstrate docking site, capable of recruiting downstream adapter proteins with Src homology-2 (SH2) domains. The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.
MET signaling pathway 
MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program. The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K), or indirectly through the scaffolding protein Gab1
Tyr 1349 and Tyr 1356 of the multisubstrate docking site are both involved in the interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2.
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signalling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways.
Activation of signal transduction 
MET engagement activates multiple signal transduction pathways:
- The RAS pathway mediates HGF-induced scattering and proliferation signals, which lead to branching morphogenesis. Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPK activity.
- The PI3K pathway is activated in two ways: PI3K can be either downstream of RAS, or it can be recruited directly through the multifunctional docking site. Activation of the PI3K pathway is currently associated with cell motility through remodeling of adhesion to the extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization, such as RAC1 and PAK. PI3K activation also triggers a survival signal due to activation of the AKT pathway.
- The STAT pathway, together with the sustained MAPK activation, is necessary for the HGF-induced branching morphogenesis. MET activates the STAT3 transcription factor directly, through an SH2 domain.
- The beta-catenin pathway, a key component of the Wnt signaling pathway, translocates into the nucleus following MET activation and participates in transcriptional regulation of numerous genes.
Role in development 
During embryonic development, transformation of the flat, two-layer germinal disc into a three-dimensional body depends on transition of some cells from an epithelial phenotype to spindle-shaped cells with motile behaviour, a mesenchymal phenotype. This process is referred to as epithelial-mesenchymal transition (EMT). Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others. MET is essential for embryogenesis, because MET -/- mice die in utero due to severe defects in placental development. Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.
Tissue distribution 
MET is normally expressed by epithelial cells. However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, and melanocytes. HGF expression is restricted to cells of mesenchymal origin.
Transcriptional control 
MET transcription is activated by HGF and several growth factors. MET promoter has four putative binding sites for Ets, a family of transcription factors that control several invasive growth genes. ETS1 activates MET transcription in vitro. MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen. HIF1 can bind to one of the several hypoxia response elements (HREs) in the MET promoter. Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.
Role in cancer 
MET pathway plays an important role in the development of cancer through:
- angiogenesis (sprouting of new blood vessels from pre-existing ones to supply a tumor with nutrients);
- scatter (cells dissociation due to metalloprotease production), which often leads to metastasis.
Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
Interaction with tumour suppressor genes 
PTEN (phosphatase and tensin homolog) is a tumor suppressor gene encoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities. PTEN protein phosphatase is able to interfere with MET signaling by dephosphorylating either PIP3 generated by PI3K, or the p52 isoform of SHC. SHC dephosphorylation inhibits recruitment of the GRB2 adapter to activated MET.
Cancer therapies targeting HGF/MET 
Since tumor invasion and metastasis are the main cause of death in cancer patients, interfering with MET signaling appears to be a promising therapeutic approach. A comprehensive list of HGF and MET targeted experimental therapeutics for oncology now in human clinical trials can be found here.
MET kinase inhibitors 
Kinase inhibitors are low molecular weight molecules that prevent ATP binding to MET, thus inhibiting receptor transphosphorylation and recruitment of the downstream effectors. The limitations of kinase inhibitors include the facts that they only inhibit kinase-dependent MET activation, and that none of them is fully specific for MET.
- K252a (Fermentek Biotechnology) is a staurosporine analogue isolated from Nocardiopsis sp. soil fungi, and it is a potent inhibitor of all receptor tyrosine kinases (RTKs). At nanomolar concentrations, K252a inhibits both the wild type and the mutant (M1268T) MET function.
- SU11274 (SUGEN) specifically inhibits MET kinase activity and its subsequent signaling. SU11274 is also an effective inhibitor of the M1268T and H1112Y MET mutants, but not the L1213V and Y1248H mutants. SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.
- PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation. Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752.
- ARQ197 (ArQule) is a promising selective inhibitor of MET, which entered a phase 2 clinical trial in 2008.
- Foretinib (XL880, Exelixis) targets multiple receptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of foretinib are MET, VEGFR2, and KDR. Foretinib has completed a phase 2 clinical trials with indications for papillary renal cell carcinoma, gastric cancer, and head and neck cancer.
- SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations.
- MP470 (SuperGen) is a novel inhibitor of c-KIT, MET, PDGFR, Flt3, and AXL. Phase I clinical trial of MP470 had been announced in 2007.
HGF inhibitors 
Since HGF is the only known ligand of MET, formation of a HGF:MET complex blocks MET biological activity. For this purpose, truncated HGF, anti-HGF neutralizing antibodies, and an uncleavable form of HGF have been utilized so far. The major limitation of HGF inhibitors is that they block only HGF-dependent MET activation.
- NK4 competes with HGF as it binds MET without inducing receptor activation, thus behaving as a full antagonist. NK4 is a molecule bearing the N-terminal hairpin and the four kringle domains of HGF. Moreover, NK4 is structurally similar to angiostatins, which is why it possesses anti-angiogenic activity.
- Neutralizing anti-HGF antibodies were initially tested in combination, and it was shown that at least three antibodies, acting on different HGF epitopes, are necessary to prevent MET tyrosine kinase activation. More recently, it has been demonstrated that fully human monoclonal antibodies can individually bind and neutralize human HGF, leading to regression of tumors in mouse models. Two anti-HGF antibodies are currently available: the humanized AV299 (AVEO), and the fully human AMG102 (Amgen).
- Uncleavable HGF is an engineered form of pro-HGF carrying a single amino-acid substitution, which prevents the maturation of the molecule. Uncleavable HGF is capable of blocking MET-induced biological responses by binding MET with high affinity and displacing mature HGF. Moreover, uncleavable HGF competes with the wild-type endogenous pro-HGF for the catalytic domain of proteases that cleave HGF precursors. Local and systemic expression of uncleavable HGF inhibits tumor growth and, more importantly, prevents metastasis.
Decoy MET 
Decoy MET refers to a soluble truncated MET receptor. Decoys are able to inhibit MET activation mediated by both HGF-dependent and independent mechanisms, as decoys prevent both the ligand binding and the MET receptor homodimerization. CGEN241 (Compugen) is a decoy MET that is highly efficient in inhibiting tumor growth and preventing metastasis in animal models.
Immunotherapy targeting MET 
Drugs used for immunotherapy can act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulating immune cells and altering differentiation/growth of tumor cells.
Passive immunotherapy 
Administering monoclonal antibodies (mAbs) is a form of passive immunotherapy. MAbs facilitate destruction of tumor cells by complement-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). In CDC, mAbs bind to specific antigen, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells. In ADCC, the Fab domain of a mAb binds to a tumor antigen, and Fc domain binds to Fc receptors present on effector cells (phagocytes and NK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading to phagocytosis of the tumor cell by neutrophils and macrophages. Furthermore, NK cells release cytotoxic molecules, which lyse tumor cells.
- DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces both shedding of the MET ectodomain as well as cleavage of the intracellular domain, which is successively degraded by proteasome machinery. As a consequence, on one side MET is inactivated, and on the other side the shed portion of extracellular MET hampers activation of other MET receptors, acting as a decoy. DN30 inhibits tumour growth and prevents metastasis in animal models.
- OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic and glioblastoma tumor growth and to improve survival in tumor xenograft models. OA-5D5 is produced as a recombinant protein in Escherichia coli. It is composed of murine variable domains for the heavy and light chains with human IgG1 constant domains. The antibody blocks HGF binding to MET in a competitive fashion.
Active immunotherapy 
Active immunotherapy to MET-expressing tumors can be achieved by administering cytokines, such as interferons (IFNs) and interleukins (IL-2), which triggers non-specific stimulation of numerous immune cells. IFNs have been tested as therapies for many types of cancers and have demonstrated therapeutic benefits. IL-2 has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of renal cell carcinoma and metastatic melanoma, which often have deregulated MET activity.
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- Wang, Dakun; Li Zaibo, Messing Edward M, Wu Guan (Sep. 2002). "Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM". J. Biol. Chem. (United States) 277 (39): 36216–22. doi:10.1074/jbc.M205111200. ISSN 0021-9258. PMID 12147692.
- Hiscox S, Jiang WG (1999). "Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells.". Biochem Biophys Res Commun 261 (2): 406–11. doi:10.1006/bbrc.1999.1002. PMID 10425198.
Further reading 
- Peruzzi B, Bottaro DP (2006). "Targeting the c-Met signaling pathway in cancer". Clin. Cancer Res. 12 (12): 3657–60. doi:10.1158/1078-0432.CCR-06-0818. PMID 16778093.
- Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (December 2003). "Met, metastasis, motility and more". Nat. Rev. Mol. Cell Biol. 4 (12): 915–25. doi:10.1038/nrm1261. PMID 14685170.
- Zhang YW, Vande Woude GF (February 2003). "HGF/SF-met signaling in the control of branching morphogenesis and invasion". J. Cell. Biochem. 88 (2): 408–17. doi:10.1002/jcb.10358. PMID 12520544.
- Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V, Tulashe D, Reveneau S (April 2002). "Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway". Oncogene 21 (15): 2309–19. doi:10.1038/sj.onc.1205297. PMID 11948414.
- Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS 65: 131–65. PMID 8380735.
- Maulik G, Shrikhande A, Kijima T, et al. (2002). "Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition". Cytokine Growth Factor Rev. 13 (1): 41–59. doi:10.1016/S1359-6101(01)00029-6. PMID 11750879.
- Ma PC, Maulik G, Christensen J, Salgia R (2004). "c-Met: structure, functions and potential for therapeutic inhibition". Cancer Metastasis Rev. 22 (4): 309–25. doi:10.1023/A:1023768811842. PMID 12884908.
- Knudsen BS, Edlund M (2004). "Prostate cancer and the met hepatocyte growth factor receptor". Adv. Cancer Res. Advances in Cancer Research 91: 31–67. doi:10.1016/S0065-230X(04)91002-0. ISBN 978-0-12-006691-9. PMID 15327888.
- Dharmawardana PG, Giubellino A, Bottaro DP (2005). "Hereditary papillary renal carcinoma type I". Curr. Mol. Med. 4 (8): 855–68. doi:10.2174/1566524043359674. PMID 15579033.
- Kemp LE, Mulloy B, Gherardi E (2006). "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors". Biochem. Soc. Trans. 34 (Pt 3): 414–7. doi:10.1042/BST0340414. PMID 16709175.
- Proto-Oncogene Proteins c-met at the US National Library of Medicine Medical Subject Headings (MeSH)
- UniProtKB/Swiss-Prot entry P08581: MET_HUMAN, ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB)
- A table with references to significant roles of MET in cancer