Hepatocyte growth factor receptor (HGF receptor)[5][6] is aprotein that in humans is encoded by theMETgene. The protein possessestyrosine 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.[citation needed] MET is normally expressed by cells ofepithelial origin, while expression of HGF/SF is restricted to cells ofmesenchymal origin. When HGF/SF binds its cognate receptor MET it induces its dimerization through a not yet completely understood mechanism leading to its activation.
Sometimes MET is misunderstood as of an abbreviation of Mesenchymal-Epithelial Transition. It is incorrect. The three letters of MET come from N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).[8]
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, onlystem cells andprogenitor 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. Both the overexpression of Met/HGFR, as well as itsautocrine activation by co-expression of its hepatocyte growth factor ligand, have been implicated in oncogenesis.[9][10]
MET proto-oncogene (GeneID: 4233) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7.[12]MET is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.
MET is areceptor tyrosine kinase (RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at afurin site to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by adisulfide bridge.[13]
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 withSrc homology-2 (SH2) domains.[16] The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction bothin vitro.[16][17]
MET activation by its ligandHGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers,[18] 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 asGRB2,SHC,[19]SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K),[19] or indirectly through the scaffolding protein Gab1[20]
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.[21]
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with highavidity, but lowaffinity.[22] Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signalling effectors, includingPI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways.[23]
ThePI3K pathway is activated in two ways: PI3K can be either downstream of RAS, or it can be recruited directly through the multifunctional docking site.[26] Activation of the PI3K pathway is currently associated withcell motility through remodeling of adhesion to the extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization, such asRAC1 andPAK. PI3K activation also triggers asurvival signal due to activation of theAKT pathway.[27]
Thebeta-catenin pathway, a key component of theWnt signaling pathway, translocates into the nucleus following MET activation and participates in transcriptional regulation of numerous genes.[29]
HGF/MET axis is also involved inmyocardial development. Both HGF and MET receptor mRNAs are co-expressed incardiomyocytes 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.[38] 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 theendocardial cushion occurs.[39] However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.[40]
MET transcription is activated by HGF and severalgrowth factors.[42]METpromoter has four putative binding sites forEts, a family oftranscription factors that control several invasive growth genes.[42]ETS1 activatesMET transcriptionin vitro.[43]MET transcription is activated byhypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen.[44] HIF1 can bind to one of the severalhypoxiaresponse elements (HREs) in theMET promoter.[34] Hypoxia also activates transcription factorAP-1, which is involved inMET transcription.[34]
Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) bymiR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.[46]
MET amplification has emerged as a potential biomarker of theclear cell tumor subtype.[47]
The SFARIgene database lists MET with anautism score of 2.0, which indicates that it is a strong candidate for playing a role in cases of autism. The database also identifies at least one study that found a role for MET in cases ofschizophrenia. The gene was first implicated in autism in a study that identified a polymorphism in the promoter of the MET gene.[49] The polymorphism reduces transcription by 50%. Further, the variant as an autism risk polymorphism has been replicated, and shown to be enriched in children with autism and gastrointestinal disturbances.[50] A rare mutation has been found that appears in two family members, one with autism and the other with a social and communication disorder.[51] The role of the receptor in brain development is distinct from its role in other developmental processes. Activation of the MET receptor regulates synapse formation[52][53][54][55][56] and can impact the development and function of circuits involved in social and emotional behavior.[57]
In adult mice, MET is required to protect cardiomyocytes by preventing age-relatedoxidative stress,apoptosis, fibrosis and cardiac dysfunction.[40] Moreover, MET inhibitors, such ascrizotinib 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 ofcaspases, metabolism alteration and blockage ofion channels.[58][59]
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 ofcardiac stem cells.[60][61]
PTEN (phosphatase and tensin homolog) is atumor suppressor gene encoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities.[62] PTEN proteinphosphatase is able to interfere with MET signaling by dephosphorylating either PIP3 generated byPI3K, or the p52 isoform ofSHC. SHC dephosphorylation inhibits recruitment of theGRB2 adapter to activated MET.[30]
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 foundhere.
Kinase inhibitors are low molecular weight molecules that preventATP 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.[66] SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.[67]
PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation.[68] Furthermore, some tumors harboringMET amplifications are highly sensitive to treatment with PHA-665752.[69]
Tivantinib (ArQule) is a promising selective inhibitor of MET, which entered a phase 2 clinical trial in 2008. (Failed a phase 3 in 2017)
Since HGF is the only known ligand of MET,[citation needed] blocking the formation of a HGF:MET complex blocks METbiological 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 fullantagonist. NK4 is a molecule bearing the N-terminal hairpin and the fourkringle domains of HGF. Moreover, NK4 is structurally similar toangiostatins, which is why it possesses anti-angiogenic activity.[71]
Neutralizing anti-HGF antibodies were initially tested in combination, and it was shown that at least threeantibodies, acting on different HGFepitopes, are necessary to prevent MET tyrosine kinase activation.[72] More recently, it has been demonstrated that fully humanmonoclonal antibodies can individually bind and neutralize human HGF, leading to regression of tumors in mouse models.[73] 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 ofproteases that cleave HGF precursors. Local and systemic expression of uncleavable HGF inhibits tumor growth and, more importantly, preventsmetastasis.
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 preventingmetastasis in animal models.[74]
Drugs used forimmunotherapy can act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulatingimmune cells and altering differentiation/growth of tumor cells.[75]
Administeringmonoclonal antibodies (mAbs) is a form of passive immunotherapy. MAbs facilitate destruction of tumor cells bycomplement-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). In CDC, mAbs bind to specificantigen, leading to activation of thecomplement cascade, which in turn leads to formation of pores in tumor cells. In ADCC, the Fab domain of a mAb binds to atumor antigen, and Fc domain binds to Fc receptors present on effector cells (phagocytes andNK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading tophagocytosis of the tumor cell byneutrophils andmacrophages. Furthermore,NK cells releasecytotoxic molecules, which lyse tumor cells.[75]
DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces bothshedding of the METectodomain as well as cleavage of the intracellular domain, which is successively degraded byproteasome 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 preventsmetastasis in animal models.[76]
Active immunotherapy to MET-expressing tumors can be achieved by administeringcytokines, such asinterferons (IFNs) andinterleukins (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 theU.S. Food and Drug Administration (FDA) for the treatment ofrenal cell carcinoma and metastatic melanoma, which often have deregulated MET activity.[75]
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