Hepatocyte growth factor receptor
Hepatocyte growth factor receptor (HGF receptor)[5][6] is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity.[7] 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.
HGF receptor is a single pass tyrosine kinase receptor essential for embryonic development, organogenesis and wound healing. Hepatocyte growth factor/Scatter Factor (HGF/SF) and its splicing isoform (NK1, NK2) are the only known ligands of the HGF receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF/SF is restricted to cells of mesenchymal origin. When HGF/SF binds its cognate receptor MET it induces its dimerization through a not yet completely understood mechanism leading to its activation.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (
Various mutations in the MET gene are associated with papillary renal carcinoma.[10]
Gene
MET proto-oncogene (GeneID: 4233) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7.[11] MET is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.
Protein
MET is a
Extracellular
- 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.[12]
Intracellular
A juxtamembrane segment that contains:
- A serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation[13]
- A tyrosine residue (Tyr 1003), which is responsible for MET
- 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.[15] The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.[15][16]
MET signaling pathway
MET activation by its ligand
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.[20]
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high
Activation of signal transduction
MET engagement activates multiple signal transduction pathways:
- The
- The AKT pathway.[26]
- The branching morphogenesis. MET activates the STAT3 transcription factor directly, through an SH2 domain.[27]
- 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.[28]
- The
Role in development
MET mediates a complex program known as invasive growth.
During
HGF/MET axis is also involved in myocardial development. Both HGF and MET receptor mRNAs are co-expressed in cardiomyocytes from E7.5, soon after the heart has been determined, to E9.5. Transcripts for HGF ligand and receptor are first detected before the occurrence of cardiac beating and looping, and persist throughout the looping stage, when heart morphology begins to elaborate.[37] In avian studies, HGF was found in the myocardial layer of the atrioventricular canal, in a developmental stage in which the epithelial to mesenchymal transformation (EMT) of the endocardial cushion occurs.[38] However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.[39]
Expression
Tissue distribution
MET is normally expressed by
Transcriptional control
MET transcription is activated by HGF and several
Clinical significance
Role in cancer
MET pathway plays an important role in the development of cancer through:
- activation of key oncogenic pathways (beta-catenin);
- 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.[44]
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.[45]
MET amplification has emerged as a potential biomarker of the
The amplification of the
Role in autism
The SFARIgene database lists MET with an
Role in heart function
In adult mice, MET is required to protect cardiomyocytes by preventing age-related oxidative stress, apoptosis, fibrosis and cardiac dysfunction.[39] Moreover, MET inhibitors, such as Crizotinib or PF-04254644, have been tested by short-term treatments in cellular and preclinical models, and have been shown to induce cardiomyocytes death through ROS production, activation of caspases, metabolism alteration and blockage of ion channels.[57][58]
In the injured heart, HGF/MET axis plays important roles in cardioprotection by promoting pro-survival (anti-apoptotic and anti-autophagic) effects in cardiomyocytes, angiogenesis, inhibition of fibrosis, anti-inflammatory and immunomodulatory signals, and regeneration through activation of cardiac stem cells.[59][60]
Interaction with tumour suppressor genes
PTEN
VHL
There is evidence of correlation between inactivation of
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.
- 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.[65] SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.[66]
- PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation.[67] Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752.[68]
- ARQ197(ArQule) is a promising selective inhibitor of MET, which entered a phase 2 clinical trial in 2008. (Failed a phase 3 in 2017)
- gastric cancer, and head and neck cancer[citation needed]
- SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations.
- MP470 (SuperGen) is a novel inhibitor of 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, blocking the 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.[69]
- Neutralizing anti-HGF antibodies were initially tested in combination, and it was shown that at least three ).
- 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 (
Immunotherapy targeting MET
Drugs used for
Passive immunotherapy
Administering
- 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.[74]
- OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic[75] and glioblastoma[76] 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
Interactions
Met has been shown to
See also
- c-Met inhibitors
- Tpr-met fusion protein
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000105976 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000009376 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading
- Peruzzi B, Bottaro DP (2006). "Targeting the c-Met signaling pathway in cancer". Clin. Cancer Res. 12 (12): 3657–60. 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. S2CID 19330786.
- 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. S2CID 13212355.
- 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. S2CID 22371025.
- 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, Ma PC, Morrison PT, Salgia R (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. PMID 11750879.
- Ma PC, Maulik G, Christensen J, Salgia R (2003). "c-Met: structure, functions and potential for therapeutic inhibition". Cancer Metastasis Rev. 22 (4): 309–25. S2CID 23542507.
- Knudsen BS, Edlund M (2004). "Prostate cancer and the met hepatocyte growth factor receptor". Adv. Cancer Res. Advances in Cancer Research. 91: 31–67. PMID 15327888.
- Dharmawardana PG, Giubellino A, Bottaro DP (2004). "Hereditary papillary renal carcinoma type I". Curr. Mol. Med. 4 (8): 855–68. S2CID 10928725.
- 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. PMID 16709175.
External links
- Proto-Oncogene+Proteins+c-met at the U.S. 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
- Human MET genome location and MET gene details page in the UCSC Genome Browser.
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