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Hepatocyte growth factor receptor

From Wikipedia, the free encyclopedia

MET
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesMET,MET proto-oncogene, receptor tyrosine kinase, AUTS9, HGFR, RCCP2, c-Met, DFNB97, OSFD, c-met
External IDsOMIM:164860;MGI:96969;HomoloGene:206;GeneCards:MET;OMA:MET - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4233

17295

Ensembl

ENSG00000105976

ENSMUSG00000009376

UniProt

P08581

P16056

RefSeq (mRNA)

NM_000245
NM_001127500
NM_001324401
NM_001324402

NM_008591

RefSeq (protein)

NP_000236
NP_001120972
NP_001311330
NP_001311331

n/a

Location (UCSC)Chr 7: 116.67 – 116.8 MbChr 6: 17.46 – 17.57 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Hepatocyte growth factor receptor(HGF receptor)[5][6]is aproteinthat in humans is encoded by theMETgene.The protein possessestyrosine kinaseactivity.[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 ofepithelialorigin, while expression of HGF/SF is restricted to cells ofmesenchymalorigin. 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 cellsandprogenitor cellsexpress 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 cellsare 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 itsautocrineactivation by co-expression of its hepatocyte growth factor ligand, have been implicated in oncogenesis.[9][10]

Various mutations in the MET gene are associated withpapillary renal carcinoma.[11]

Gene

[edit]

METproto-oncogene (GeneID: 4233) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7.[12]METis transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.

Protein

[edit]

MET is areceptor tyrosine kinase(RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at afurinsite to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by adisulfide bridge.[13]

Extracellular

[edit]
  • Region of homology tosemaphorins(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.[13]

Intracellular

[edit]

A juxtamembrane segment that contains:

  • A serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation[14]
  • A tyrosine residue (Tyr 1003), which is responsible for METpolyubiquitination,endocytosis,and degradation upon interaction with theubiquitin ligaseCBL[15]
  • 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 signaling pathway

[edit]

MET activation by its ligandHGFinduces 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]

Activation of signal transduction

[edit]

MET engagement activates multiplesignal transductionpathways:

Role in development

[edit]

MET mediates a complex program known as invasive growth.[27]Activation of MET triggersmitogenesis,andmorphogenesis.[32][33]

Duringembryonic development,transformation of the flat, two-layergerminal discinto a three-dimensional body depends on transition of some cells from anepithelialphenotypeto spindle-shaped cells with motile behaviour, amesenchymalphenotype.This process is referred to asepithelial-mesenchymal transition(EMT).[34]Later in embryonic development, MET is crucial forgastrulation,angiogenesis,myoblastmigration,bone remodeling,andnervesprouting among others.[35]MET is essential forembryogenesis,becauseMET−/−mice diein uterodue to severe defects in placental development.[36]Along withEctodysplasin A,it has been shown to be involved in the differentiation of anatomical placodes, precursors of scales, feathers and hair follicles in vertebrates.[37]Furthermore, MET is required for such critical processes asliverregeneration andwound healingduring adulthood.[27]

HGF/MET axis is also involved inmyocardial development.Both HGF and MET receptor mRNAs are co-expressed incardiomyocytesfrom 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 cushionoccurs.[39]However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.[40]

Expression

[edit]

Tissue distribution

[edit]

MET is normally expressed byepithelial cells.[27]However, MET is also found onendothelial cells,neurons,hepatocytes,hematopoieticcells,melanocytesand neonatal cardiomyocytes.[33][41]HGF expression is restricted to cells ofmesenchymalorigin.[34]

Transcriptional control

[edit]

METtranscription is activated by HGF and severalgrowth factors.[42]METpromoterhas four putative binding sites forEts,a family oftranscription factorsthat control several invasive growth genes.[42]ETS1activatesMETtranscriptionin vitro.[43]METtranscription 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 theMETpromoter.[34]Hypoxia also activates transcription factorAP-1,which is involved inMETtranscription.[34]

Clinical significance

[edit]

Role in cancer

[edit]

MET pathway plays an important role in the development of cancer through:

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 tumorsubtype.[47]

The amplification of thecell surface receptorMET often drives resistance toanti-EGFR therapiesincolorectal cancer.[48]

Role in autism

[edit]

The SFARIgene database lists MET with anautismscore 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]

Role in heart function

[edit]

In adult mice, MET is required to protect cardiomyocytes by preventing age-relatedoxidative stress,apoptosis,fibrosis and cardiac dysfunction.[40]Moreover, MET inhibitors, such ascrizotinibor 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]

Interaction with tumour suppressor genes

[edit]

PTEN

[edit]

PTEN(phosphatase and tensin homolog) is atumor suppressor geneencoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities.[62]PTEN proteinphosphataseis able to interfere with MET signaling by dephosphorylating either PIP3generated byPI3K,or the p52 isoform ofSHC.SHC dephosphorylation inhibits recruitment of theGRB2adapter to activated MET.[30]

VHL

[edit]

There is evidence of correlation between inactivation ofVHLtumor suppressor geneand increased MET signaling inrenal cell carcinoma(RCC) and also in malignant transformations of the heart.[63][64]

Cancer therapies targeting HGF/MET

[edit]

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.

MET kinase inhibitors

[edit]
Further information:c-Met inhibitor

Kinase inhibitors are low molecular weight molecules that preventATPbinding 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(FermentekBiotechnology) is astaurosporineanalogue isolated fromNocardiopsissp. soilfungi,and it is a potent inhibitor of allreceptor tyrosine kinases(RTKs). At nanomolar concentrations, K252a inhibits both thewild typeand the mutant (M1268T) MET function.[65]
  • 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 harboringMETamplifications 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)
  • Foretinib(XL880, Exelixis) targets multiplereceptor tyrosine kinases(RTKs) with growth-promoting and angiogenic properties. The primary targets of foretinib are MET,VEGFR2,andKDR.Foretinib has completed a phase 2 clinical trials with indications for papillaryrenal cell carcinoma,gastric cancer,andhead and neck cancer[citation needed]
  • SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations.
  • MP470 (SuperGen) is a novel inhibitor ofc-KIT,MET,PDGFR,Flt3, andAXL.Phase I clinical trial of MP470 had been announced in 2007.
  • Vebreltinib,approved in China for the treatment of non-small-cell lung cancer.[70]

HGF inhibitors

[edit]

Since HGF is the only known ligand of MET, 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 domainsof 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 antibodiescan 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 ofproteasesthat cleave HGF precursors. Local and systemic expression of uncleavable HGF inhibits tumor growth and, more importantly, preventsmetastasis.

Decoy MET

[edit]

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 preventingmetastasisin animal models.[74]

Immunotherapy targeting MET

[edit]

Drugs used forimmunotherapycan act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulatingimmune cellsand altering differentiation/growth of tumor cells.[75]

Passive immunotherapy

[edit]

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 (phagocytesandNK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading tophagocytosisof the tumor cell byneutrophilsandmacrophages.Furthermore,NK cellsreleasecytotoxicmolecules, which lyse tumor cells.[75]

  • DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces bothsheddingof the METectodomainas well as cleavage of the intracellular domain, which is successively degraded byproteasomemachinery. 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 preventsmetastasisin animal models.[76]
  • OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic[77]andglioblastoma[78]tumor growth and to improve survival intumor xenograft models.OA-5D5 is produced as arecombinant proteininEscherichia coli.It is composed of murinevariable domainsfor theheavyandlight chainswith human IgG1 constant domains. The antibody blocks HGF binding to MET in a competitive fashion.

Active immunotherapy

[edit]

Active immunotherapyto 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 carcinomaand metastatic melanoma, which often have deregulated MET activity.[75]

Interactions

[edit]

Met has been shown tointeractwith:

See also

[edit]

References

[edit]
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Further reading

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