hepatocyte growth factor receptor

Hepatocyte growth factor receptor (HGF receptor){{cite journal | vauthors = Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA | author-link7 = Stuart A. Aaronson | title = Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product | journal = Science | volume = 251 | issue = 4995 | pages = 802–4 | date = February 1991 | pmid = 1846706 | doi = 10.1126/science.1846706 | bibcode = 1991Sci...251..802B }}{{cite journal | vauthors = Galland F, Stefanova M, Lafage M, Birnbaum D | title = Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15----q23 | journal = Cytogenet. Cell Genet. | volume = 60 | issue = 2 | pages = 114–6 | year = 1992 | pmid = 1611909 | doi = 10.1159/000133316 }} is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity.{{cite journal | vauthors = Cooper CS | title = The met oncogene: from detection by transfection to transmembrane receptor for hepatocyte growth factor | journal = Oncogene | volume = 7 | issue = 1 | pages = 3–7 | date = January 1992 | pmid = 1531516 }} 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|date=March 2025}} 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.

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). {{cite journal | vauthors = Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF | title = Molecular cloning of a new transforming gene from a chemically transformed human cell line | journal = Nature | volume = 311 | issue = 5981 | pages = 29–33 | date = 6 September 1984 | pmid = 6590967 | doi = 10.1038/311029a0 }}

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. Both the overexpression of Met/HGFR, as well as its autocrine activation by co-expression of its hepatocyte growth factor ligand, have been implicated in oncogenesis.{{cite journal | vauthors = Johnson M, Koukoulis G, Kochhar K, Kubo C, Nakamura T, Iyer A | title = Selective tumorigenesis in non-parenchymal liver epithelial cell lines by hepatocyte growth factor transfection | journal = Cancer Letters | volume = 96 | issue = 1 | pages = 37–48 | date = Sep 1995 | pmid = 7553606 | doi=10.1016/0304-3835(95)03915-j}}{{cite journal | vauthors = Kochhar KS, Johnson ME, Volpert O, Iyer AP | title = Evidence for autocrine basis of transformation in NIH-3T3 cells transfected with met/HGF receptor gene | journal = Growth Factors | volume = 12 | issue = 4 | pages = 303–13 | date = 1995 | pmid = 8930021 | doi=10.3109/08977199509028968}}

Various mutations in the MET gene are associated with papillary renal carcinoma.{{Cite web| title = Entrez Gene: MET met proto-oncogene (hepatocyte growth factor receptor)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4233}}

Gene

MET proto-oncogene ([https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4233&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum GeneID: 4233]) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7.{{cite journal | vauthors = Dean M, Park M, Le Beau MM, Robins TS, Diaz MO, Rowley JD, Blair DG, Vande Woude GF | title = The human met oncogene is related to the tyrosine kinase oncogenes | journal = Nature | volume = 318 | issue = 6044 | pages = 385–8 | year = 1985 | pmid = 4069211 | doi = 10.1038/318385a0 | bibcode = 1985Natur.318..385D | s2cid = 4359961 | url = https://zenodo.org/record/1233043 }} 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 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.{{cite journal | vauthors = Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF | title = Met, metastasis, motility and more | journal = Nat. Rev. Mol. Cell Biol. | volume = 4 | issue = 12 | pages = 915–25 | date = December 2003 | pmid = 14685170 | doi = 10.1038/nrm1261 | s2cid = 19330786 }}

= 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.

= Intracellular =

A juxtamembrane segment that contains:

A serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation{{cite journal | vauthors = Gandino L, Longati P, Medico E, Prat M, Comoglio PM | title = Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase | journal = J. Biol. Chem. | volume = 269 | issue = 3 | pages = 1815–20 | date = January 1994 | doi = 10.1016/S0021-9258(17)42099-0 | pmid = 8294430 | doi-access = free }}
A tyrosine residue (Tyr 1003), which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL{{cite journal | vauthors = Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M | title = Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein | journal = Mol. Cell | volume = 8 | issue = 5 | pages = 995–1004 | date = November 2001 | pmid = 11741535 | doi = 10.1016/S1097-2765(01)00378-1 | doi-access = free }}
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.{{cite journal | vauthors = Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM | title = A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family | journal = Cell | volume = 77 | issue = 2 | pages = 261–71 | date = April 1994 | pmid = 7513258 | doi = 10.1016/0092-8674(94)90318-2 | s2cid = 23383203 }} The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.{{cite journal | vauthors = Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C | title = Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development | journal = Cell | volume = 87 | issue = 3 | pages = 531–42 | date = November 1996 | pmid = 8898205 | doi = 10.1016/S0092-8674(00)81372-0 | s2cid = 12943699 | doi-access = free }}

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,{{cite journal | vauthors = Johnson M, Kochhar K, Nakamura T, Iyer A | title = Hepatocyte growth factor-induced signal transduction in two normal mouse epithelial cell lines | journal = Biochemistry and Molecular Biology International | volume = 36 | issue = 3 | pages = 465–74 | date = Jul 1995 | pmid = 7549943 }} 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,{{cite journal | vauthors = Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG | title = The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein | journal = Oncogene | volume = 10 | issue = 8 | pages = 1631–8 | date = April 1995 | pmid = 7731718 }} SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K), or indirectly through the scaffolding protein Gab1{{cite journal | vauthors = Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W | title = Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis | journal = Nature | volume = 384 | issue = 6605 | pages = 173–6 | date = November 1996 | pmid = 8906793 | doi = 10.1038/384173a0 | bibcode = 1996Natur.384..173W | s2cid = 4357372 }}

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.{{cite journal | vauthors = Furge KA, Zhang YW, Vande Woude GF | title = Met receptor tyrosine kinase: enhanced signaling through adapter proteins | journal = Oncogene | volume = 19 | issue = 49 | pages = 5582–9 | date = November 2000 | pmid = 11114738 | doi = 10.1038/sj.onc.1203859 | s2cid = 22385297 | doi-access = }}

GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity.{{cite journal | vauthors = Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM | title = Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling | journal = Oncogene | volume = 20 | issue = 2 | pages = 156–66 | date = January 2001 | pmid = 11313945 | doi = 10.1038/sj.onc.1204047 | s2cid = 35447713 | doi-access = }} 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.{{cite journal | vauthors = Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM | title = Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis | journal = Oncogene | volume = 19 | issue = 12 | pages = 1509–18 | date = March 2000 | pmid = 10734310 | doi = 10.1038/sj.onc.1203514 | s2cid = 22727382 | doi-access = }}

=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.{{cite journal|author6-link=Keith E. Mostov | vauthors = O'Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE | title = ERK and MMPs sequentially regulate distinct stages of epithelial tubule development | journal = Dev. Cell | volume = 7 | issue = 1 | pages = 21–32 | date = July 2004 | pmid = 15239951 | doi = 10.1016/j.devcel.2004.06.001 | doi-access = free }} Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPK activity.{{cite journal | vauthors = Marshall CJ | title = Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation | journal = Cell | volume = 80 | issue = 2 | pages = 179–85 | date = January 1995 | pmid = 7834738 | doi = 10.1016/0092-8674(95)90401-8 | s2cid = 8995643 | doi-access = free }}
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.{{cite journal | vauthors = Graziani A, Gramaglia D, Cantley LC, Comoglio PM | title = The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase | journal = J. Biol. Chem. | volume = 266 | issue = 33 | pages = 22087–90 | date = November 1991 | doi = 10.1016/S0021-9258(18)54536-1 | pmid = 1718989 | doi-access = free }} 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.{{cite journal | vauthors = Gentile A, Trusolino L, Comoglio PM | title = The Met tyrosine kinase receptor in development and cancer | journal = Cancer Metastasis Rev. | volume = 27 | issue = 1 | pages = 85–94 | date = March 2008 | pmid = 18175071 | doi = 10.1007/s10555-007-9107-6 | s2cid = 33076010 }}
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.{{cite journal | vauthors = Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM | title = Induction of epithelial tubules by growth factor HGF depends on the STAT pathway | journal = Nature | volume = 391 | issue = 6664 | pages = 285–8 | date = January 1998 | pmid = 9440692 | doi = 10.1038/34657 | bibcode = 1998Natur.391..285B | s2cid = 30330705 }}
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.{{cite journal | vauthors = Monga SP, Mars WM, Pediaditakis P, Bell A, Mulé K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK | title = Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes | journal = Cancer Res. | volume = 62 | issue = 7 | pages = 2064–71 | date = April 2002 | pmid = 11929826 }}
The Notch pathway, through transcriptional activation of Delta ligand (see DLL3).{{cite journal | vauthors = Gude NA, Emmanuel G, Wu W, Cottage CT, Fischer K, Quijada P, Muraski JA, Alvarez R, Rubio M, Schaefer E, Sussman MA | title = Activation of Notch-mediated protective signaling in the myocardium | journal = Circ. Res. | volume = 102 | issue = 9 | pages = 1025–35 | date = May 2008 | pmid = 18369158 | doi = 10.1161/CIRCRESAHA.107.164749 | pmc = 3760732 }}

Role in development

MET mediates a complex program known as invasive growth. Activation of MET triggers mitogenesis, and morphogenesis.{{cite journal | vauthors = Johnson M, Koukoulis G, Matsumoto K, Nakamura T, Iyer A | title = Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells | journal = Hepatology | volume = 17 | issue = 6 | pages = 1052–61 | date = Jun 1993 | pmid = 8514254 | doi=10.1016/0270-9139(93)90122-4| doi-access = free }}{{Cite web| url = http://www.healthvalue.net/cmetfields.html | title = he fields of HGF/c-Met involvement | publisher = HealthValue | archive-url =https://web.archive.org/web/20070927043855/http://www.healthvalue.net/cmetfields.html| archive-date =2007-09-27| url-status=dead | access-date = 2009-06-13}}

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).{{cite journal | vauthors = Boccaccio C, Comoglio PM | title = Invasive growth: a MET-driven genetic programme for cancer and stem cells | journal = Nat. Rev. Cancer | volume = 6 | issue = 8 | pages = 637–45 | date = August 2006 | pmid = 16862193 | doi = 10.1038/nrc1912 | s2cid = 396385 }} Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others.{{cite journal | vauthors = Birchmeier C, Gherardi E | title = Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase | journal = Trends Cell Biol. | volume = 8 | issue = 10 | pages = 404–10 | date = October 1998 | pmid = 9789329 | doi = 10.1016/S0962-8924(98)01359-2 }} MET is essential for embryogenesis, because MET ^−/− mice die in utero due to severe defects in placental development.{{cite journal | vauthors = Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N | title = Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor | journal = Nature | volume = 373 | issue = 6516 | pages = 702–5 | date = February 1995 | pmid = 7854453 | doi = 10.1038/373702a0 | bibcode = 1995Natur.373..702U | s2cid = 4361262 }} Along with Ectodysplasin A, it has been shown to be involved in the differentiation of anatomical placodes, precursors of scales, feathers and hair follicles in vertebrates.{{cite journal | vauthors = Barrow-McGee R, Kishi N, Joffre C, Ménard L, Hervieu A, Bakhouche BA, Noval AJ, Mai A, Guzmán C, Robert-Masson L, Iturrioz X, Hulit J, Brennan CH, Hart IR, Parker PJ, Ivaska J, Kermorgant S | title = Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes | journal = Nature Communications | volume = 7 | pages = 11942 | year = 2016 | pmid = 27336951 | doi = 10.1038/ncomms11942 | pmc=4931016| bibcode = 2016NatCo...711942B }} Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.

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.{{cite journal | vauthors = Rappolee DA, Iyer A, Patel Y | title = Hepatocyte growth factor and its receptor are expressed in cardiac myocytes during early cardiogenesis | journal = Circulation Research | volume = 78 | issue = 6 | pages = 1028–36 | date = Jun 1996 | pmid = 8635233 | doi = 10.1161/01.RES.78.6.1028 | url = https://digitalcommons.wayne.edu/med_obgyn/5 }} 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.{{cite journal | vauthors = Song W, Majka SM, McGuire PG | title = Hepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression | journal = Developmental Dynamics | volume = 214 | issue = 1 | pages = 92–100 | year = 1999 | pmid = 9915579 | doi = 10.1002/(SICI)1097-0177(199901)214:1<92::AID-DVDY9>3.0.CO;2-X | doi-access = free }} However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.{{cite journal | vauthors = Arechederra M, Carmona R, González-Nuñez M, Gutiérrez-Uzquiza A, Bragado P, Cruz-González I, Cano E, Guerrero C, Sánchez A, López-Novoa JM, Schneider MD, Maina F, Muñoz-Chápuli R, Porras A | title = Met signaling in cardiomyocytes is required for normal cardiac function in adult mice | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1832 | issue = 12 | pages = 2204–15 | date = Dec 2013 | pmid = 23994610 | doi = 10.1016/j.bbadis.2013.08.008 | url = http://digital.csic.es/bitstream/10261/134355/5/Met%20signaling.pdf | doi-access = free }}

Expression

= Tissue distribution =

MET is normally expressed by epithelial cells. However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, melanocytes and neonatal cardiomyocytes.{{cite journal | vauthors = Leo C, Sala V, Morello M, Chiribiri A, Riess I, Mancardi D, Schiaffino S, Ponzetto C, Crepaldi T | title = Activated Met signalling in the developing mouse heart leads to cardiac disease | journal = PLOS ONE | volume = 6 | issue = 2 | pages = e14675 | date = 2011-02-09 | pmid = 21347410 | pmc = 3036588 | doi = 10.1371/journal.pone.0014675 | doi-access = free | bibcode = 2011PLoSO...614675L }} HGF expression is restricted to cells of mesenchymal origin.

= Transcriptional control =

MET transcription is activated by HGF and several growth factors.{{cite journal | vauthors = Shirasaki F, Makhluf HA, LeRoy C, Watson DK, Trojanowska M | title = Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter | journal = Oncogene | volume = 18 | issue = 54 | pages = 7755–64 | date = December 1999 | pmid = 10618716 | doi = 10.1038/sj.onc.1203360 | doi-access = free }} 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.{{cite journal | vauthors = Gambarotta G, Boccaccio C, Giordano S, Andŏ M, Stella MC, Comoglio PM | title = Ets up-regulates MET transcription | journal = Oncogene | volume = 13 | issue = 9 | pages = 1911–7 | date = November 1996 | pmid = 8934537 }} MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen.{{cite journal | vauthors = Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM | title = Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene | journal = Cancer Cell | volume = 3 | issue = 4 | pages = 347–61 | date = April 2003 | pmid = 12726861 | doi = 10.1016/S1535-6108(03)00085-0 | doi-access = free }} 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.

Clinical significance

= Role in cancer =

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

activation of key oncogenic pathways (RAS, PI3K, STAT3, 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.{{Cite web| url = http://www.healthvalue.net/c-metandcancer.html | title = HGF/c-Met and cancer | publisher = HealthValue | archive-url =https://web.archive.org/web/20070927043723/http://www.healthvalue.net/c-metandcancer.html| archive-date =2007-09-27| url-status=dead | access-date = 2009-06-13}}

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.{{cite journal | vauthors = Kim S, Lee UJ, Kim MN, Lee EJ, Kim JY, Lee MY, Choung S, Kim YJ, Choi YC | title = MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2) | journal = J. Biol. Chem. | volume = 283 | issue = 26 | pages = 18158–66 | date = June 2008 | pmid = 18456660 | doi = 10.1074/jbc.M800186200 |doi-access=free }}

MET amplification has emerged as a potential biomarker of the clear cell tumor subtype.{{cite journal | vauthors = del Carmen MG, Birrer M, Schorge JO | title = Clear cell carcinoma of the ovary: a review of the literature | journal = Gynecol. Oncol. | volume = 126 | issue = 3 | pages = 481–90 | date = September 2012 | pmid = 22525820 | doi = 10.1016/j.ygyno.2012.04.021 }}

The amplification of the cell surface receptor MET often drives resistance to anti-EGFR therapies in colorectal cancer.{{cite journal |author1-link=Alberto Bardelli | vauthors = Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S | title = Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer | journal = Cancer Discov | volume = 3 | issue = 6 | pages = 658–73 | date = June 2013 | pmid = 23729478 | pmc = 4078408 | doi = 10.1158/2159-8290.CD-12-0558 }}

= Role in autism =

The SFARIgene database lists MET with an autism 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 of schizophrenia. The gene was first implicated in autism in a study that identified a polymorphism in the promoter of the MET gene.{{cite journal | vauthors = Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P | title = A genetic variant that disrupts MET transcription is associated with autism | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 45 | pages = 16834–9 | year = 2006 | pmid = 17053076 | doi = 10.1073/pnas.0605296103 | pmc=1838551| doi-access = free }} 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.{{cite journal | vauthors = Campbell DB, Buie TM, Winter H, Bauman M, Sutcliffe JS, Perrin JM, Levitt P | title = Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions | journal = Pediatrics | volume = 123 | issue = 3 | pages = 1018–24 | year = 2009 | pmid = 19255034 | doi = 10.1542/peds.2008-0819 | s2cid = 5395283 }} A rare mutation has been found that appears in two family members, one with autism and the other with a social and communication disorder.{{cite journal | vauthors = Lambert N, Wermenbol V, Pichon B, Acosta S, van den Ameele J, Perazzolo C, Messina D, Musumeci MF, Dessars B, De Leener A, Abramowicz M, Vilain C | title = A familial heterozygous null mutation of MET in autism spectrum disorder | journal = Autism Res | volume = 7 | issue = 5 | pages = 617–22 | year = 2014 | pmid = 24909855 | doi = 10.1002/aur.1396 | s2cid = 5608613 }} 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{{cite journal | vauthors = Qiu S, Lu Z, Levitt P | title = MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus | journal = J. Neurosci. | volume = 34 | issue = 49 | pages = 16166–79 | year = 2014 | pmid = 25471559 | doi = 10.1523/JNEUROSCI.2580-14.2014 | pmc=4252539}}{{cite journal | vauthors = Eagleson KL, Milner TA, Xie Z, Levitt P | title = Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus | journal = J. Comp. Neurol. | volume = 521 | issue = 14 | pages = 3241–59 | year = 2013 | pmid = 23787772 | pmc = 3942873 | doi = 10.1002/cne.23343 }}{{cite journal | vauthors = Judson MC, Eagleson KL, Levitt P | title = A new synaptic player leading to autism risk: Met receptor tyrosine kinase | journal = J Neurodev Disord | volume = 3 | issue = 3 | pages = 282–92 | year = 2011 | pmid = 21509596 | pmc = 3261279 | doi = 10.1007/s11689-011-9081-8 }}{{cite journal | vauthors = Qiu S, Anderson CT, Levitt P, Shepherd GM | title = Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase | journal = J. Neurosci. | volume = 31 | issue = 15 | pages = 5855–64 | year = 2011 | pmid = 21490227 | pmc = 3086026 | doi = 10.1523/JNEUROSCI.6569-10.2011 }}{{cite journal | vauthors = Judson MC, Eagleson KL, Wang L, Levitt P | title = Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain | journal = J. Comp. Neurol. | volume = 518 | issue = 21 | pages = 4463–78 | year = 2010 | pmid = 20853516 | pmc = 2952412 | doi = 10.1002/cne.22467 }} and can impact the development and function of circuits involved in social and emotional behavior.{{cite journal | pmid = 22958829 | doi=10.1016/j.neuron.2012.07.010 | volume=75 | issue=5 | title=Autism-associated promoter variant in MET impacts functional and structural brain networks | pmc=3454529 | journal=Neuron | pages=904–15 | vauthors=Rudie JD, Hernandez LM, Brown JA, Beck-Pancer D, Colich NL, Gorrindo P, Thompson PM, Geschwind DH, Bookheimer SY, Levitt P, Dapretto M| year=2012 }}

= Role in heart function =

In adult mice, MET is required to protect cardiomyocytes by preventing age-related oxidative stress, apoptosis, fibrosis and cardiac dysfunction. 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.{{cite journal | vauthors = Doherty KR, Wappel RL, Talbert DR, Trusk PB, Moran DM, Kramer JW, Brown AM, Shell SA, Bacus S | title = Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes | journal = Toxicology and Applied Pharmacology | volume = 272 | issue = 1 | pages = 245–55 | date = October 2013 | pmid = 23707608 | doi = 10.1016/j.taap.2013.04.027 }}{{cite journal | vauthors = Aguirre SA, Heyen JR, Collette W, Bobrowski W, Blasi ER | title = Cardiovascular effects in rats following exposure to a receptor tyrosine kinase inhibitor | journal = Toxicologic Pathology | volume = 38 | issue = 3 | pages = 416–28 | date = April 2010 | pmid = 20231546 | doi = 10.1177/0192623310364027 | doi-access = free }}

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.{{cite journal | vauthors = Schmoldt A, Benthe HF, Haberland G, Scott WA, Mahoney E, Pounds JG, Long GJ, Rosen JF | title = Cellular and molecular toxicity of lead in bone | journal = Environmental Health Perspectives | volume = 91 | issue = 17 | pages = 17–32 | date = February 1991 | pmid = 2040247 | pmc=1519349| doi = 10.1289/ehp.919117 }}{{cite journal | vauthors = Sala V, Crepaldi T | title = Novel therapy for myocardial infarction: can HGF/Met be beneficial? | journal = Cellular and Molecular Life Sciences | volume = 68 | issue = 10 | pages = 1703–17 | date = May 2011 | pmid = 21327916 | doi = 10.1007/s00018-011-0633-6 | s2cid = 32535928 | pmc = 11114731 }}

Interaction with tumour suppressor genes

= ''PTEN'' =

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.{{cite journal | vauthors = Maehama T, Dixon JE | title = The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate | journal = J. Biol. Chem. | volume = 273 | issue = 22 | pages = 13375–8 | date = May 1998 | pmid = 9593664 | doi = 10.1074/jbc.273.22.13375 | doi-access = free }} 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.{{cite journal | vauthors = Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J | title = Regulation of c-Met-dependent gene expression by PTEN | journal = Oncogene | volume = 23 | issue = 57 | pages = 9173–82 | date = December 2004 | pmid = 15516982 | doi = 10.1038/sj.onc.1208146 | s2cid = 7623249 | doi-access = }}

= ''VHL'' =

There is evidence of correlation between inactivation of VHL tumor suppressor gene and increased MET signaling in renal cell carcinoma (RCC) and also in malignant transformations of the heart.{{cite journal | vauthors = Morris MR, Gentle D, Abdulrahman M, Maina EN, Gupta K, Banks RE, Wiesener MS, Kishida T, Yao M, Teh B, Latif F, Maher ER | title = Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma | journal = Cancer Res. | volume = 65 | issue = 11 | pages = 4598–606 | date = June 2005 | pmid = 15930277 | doi = 10.1158/0008-5472.CAN-04-3371 | doi-access = free }}{{cite journal | vauthors = Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, Jovin IS, Pypaert M, Johnson RS, Giordano FJ | title = Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein | journal = Molecular and Cellular Biology | volume = 28 | issue = 11 | pages = 3790–803 | date = June 2008 | pmid = 18285456 | pmc = 2423296 | doi = 10.1128/MCB.01580-07 }}

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 [https://ccrod.cancer.gov/confluence/display/CCRHGF/Home 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.{{cite journal | vauthors = Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C | title = K252a inhibits the oncogenic properties of Met, the HGF receptor | journal = Oncogene | volume = 21 | issue = 32 | pages = 4885–93 | date = July 2002 | pmid = 12118367 | doi = 10.1038/sj.onc.1205622 | s2cid = 32305287 | doi-access = }}
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.{{cite journal | vauthors = Berthou S, Aebersold DM, Schmidt LS, Stroka D, Heigl C, Streit B, Stalder D, Gruber G, Liang C, Howlett AR, Candinas D, Greiner RH, Lipson KE, Zimmer Y | title = The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants | journal = Oncogene | volume = 23 | issue = 31 | pages = 5387–93 | date = July 2004 | pmid = 15064724 | doi = 10.1038/sj.onc.1207691 | s2cid = 12545344 | doi-access = }} SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.{{cite journal | vauthors = Wang X, Le P, Liang C, Chan J, Kiewlich D, Miller T, Harris D, Sun L, Rice A, Vasile S, Blake RA, Howlett AR, Patel N, McMahon G, Lipson KE | title = Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion | journal = Mol. Cancer Ther. | volume = 2 | issue = 11 | pages = 1085–92 | date = November 2003 | pmid = 14617781 }}
PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation.{{cite journal | vauthors = Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB | title = A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo | journal = Cancer Res. | volume = 63 | issue = 21 | pages = 7345–55 | date = November 2003 | pmid = 14612533 }} Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752.{{cite journal | vauthors = Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA | title = Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 7 | pages = 2316–21 | date = February 2006 | pmid = 16461907 | pmc = 1413705 | doi = 10.1073/pnas.0508776103 | doi-access = free | bibcode = 2006PNAS..103.2316S }}
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 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{{Citation needed|date=June 2021}}
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.
Vebreltinib, approved in China for the treatment of non-small-cell lung cancer.{{cite news | url = https://www.onclive.com/view/vebreltinib-receives-approval-in-china-for-met-exon-14-nsclc | website = onclive.com | title = Vebreltinib Receives Approval in China For MET Exon 14+ NSCLC | date = November 16, 2023 }}

= HGF inhibitors =

Since HGF is the only known ligand of MET,{{citation needed|date=March 2025}} 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.{{cite journal | vauthors = Matsumoto K, Nakamura T | title = NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics | journal = Cancer Sci. | volume = 94 | issue = 4 | pages = 321–7 | date = April 2003 | pmid = 12824898 | doi = 10.1111/j.1349-7006.2003.tb01440.x | s2cid = 24806218 | pmc = 11160298 }}
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.{{cite journal | vauthors = Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF | title = Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 13 | pages = 7443–8 | date = June 2001 | pmid = 11416216 | pmc = 34688 | doi = 10.1073/pnas.131200498 | doi-access = free | bibcode = 2001PNAS...98.7443C }} 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.{{cite journal | vauthors = Burgess T, Coxon A, Meyer S, Sun J, Rex K, Tsuruda T, Chen Q, Ho SY, Li L, Kaufman S, McDorman K, Cattley RC, Sun J, Elliott G, Zhang K, Feng X, Jia XC, Green L, Radinsky R, Kendall R | title = Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors | journal = Cancer Res. | volume = 66 | issue = 3 | pages = 1721–9 | date = February 2006 | pmid = 16452232 | doi = 10.1158/0008-5472.CAN-05-3329 | doi-access = }} 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.{{cite journal | vauthors = Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, Comoglio PM | title = Targeting the tumor and its microenvironment by a dual-function decoy Met receptor | journal = Cancer Cell | volume = 6 | issue = 1 | pages = 61–73 | date = July 2004 | pmid = 15261142 | doi = 10.1016/j.ccr.2004.05.032 | doi-access = free }}

= 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.{{cite journal | vauthors = Reang P, Gupta M, Kohli K | title = Biological response modifiers in cancer | journal = MedGenMed | volume = 8 | issue = 4 | pages = 33 | year = 2006 | pmid = 17415315 | pmc = 1868326 }}

== 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.{{cite journal | vauthors = Petrelli A, Circosta P, Granziero L, Mazzone M, Pisacane A, Fenoglio S, Comoglio PM, Giordano S | title = Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 13 | pages = 5090–5 | date = March 2006 | pmid = 16547140 | pmc = 1458799 | doi = 10.1073/pnas.0508156103 | doi-access = free | bibcode = 2006PNAS..103.5090P }}
OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic{{cite journal | vauthors = Jin H, Yang R, Zheng Z, Romero M, Ross J, Bou-Reslan H, Carano RA, Kasman I, Mai E, Young J, Zha J, Zhang Z, Ross S, Schwall R, Colbern G, Merchant M | title = MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival | journal = Cancer Res. | volume = 68 | issue = 11 | pages = 4360–8 | date = June 2008 | pmid = 18519697 | doi = 10.1158/0008-5472.CAN-07-5960 | doi-access = free }} and glioblastoma{{cite journal | vauthors = Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K | title = A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo | journal = Clin. Cancer Res. | volume = 12 | issue = 20 Pt 1 | pages = 6144–52 | date = October 2006 | pmid = 17062691 | doi = 10.1158/1078-0432.CCR-05-1418 | doi-access = free }} 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.

Interactions

Met has been shown to interact with:

CDH1,{{cite journal | vauthors = Davies G, Jiang WG, Mason MD | title = HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells | journal = Int. J. Mol. Med. | volume = 7 | issue = 4 | pages = 385–8 | year = 2001 | pmid = 11254878 | doi = 10.3892/ijmm.7.4.385 }}
Cbl gene,{{cite journal | vauthors = Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S | title = The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met | journal = Nature | volume = 416 | issue = 6877 | pages = 187–90 | year = 2002 | pmid = 11894096 | doi = 10.1038/416187a | bibcode = 2002Natur.416..187P | s2cid = 4389099 }}{{cite journal | vauthors = Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J | title = Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates | journal = EMBO J. | volume = 27 | issue = 5 | pages = 804–16 | year = 2008 | pmid = 18273061 | pmc = 2265755 | doi = 10.1038/emboj.2008.18 }}
GLMN,{{cite journal | vauthors = Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T | title = Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor | journal = J. Biol. Chem. | volume = 276 | issue = 49 | pages = 46632–8 | year = 2001 | pmid = 11571281 | doi = 10.1074/jbc.M104323200 | doi-access = free }}
Grb2,{{cite journal | vauthors = Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narsimhan R, Comoglio P | title = Specific uncoupling of GRB2 from the Met receptor. Differential effects on transformation and motility | journal = J. Biol. Chem. | volume = 271 | issue = 24 | pages = 14119–23 | year = 1996 | pmid = 8662889 | doi = 10.1074/jbc.271.24.14119 | doi-access = free }}{{cite journal | vauthors = Liang Q, Mohan RR, Chen L, Wilson SE | title = Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways | journal = Invest. Ophthalmol. Vis. Sci. | volume = 39 | issue = 8 | pages = 1329–38 | year = 1998 | pmid = 9660480 }}
Hepatocyte growth factor,{{cite journal | vauthors = Comoglio PM | title = Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells | journal = EXS | volume = 65 | pages = 131–65 | year = 1993 | pmid = 8380735 }}{{cite journal | vauthors = Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK | title = Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor | journal = EMBO J. | volume = 10 | issue = 10 | pages = 2867–78 | year = 1991 | pmid = 1655405 | pmc = 452997 | doi = 10.1002/j.1460-2075.1991.tb07836.x}}
PTPmu,{{cite journal | vauthors = Hiscox S, Jiang WG | title = Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells | journal = Biochem. Biophys. Res. Commun. | volume = 261 | issue = 2 | pages = 406–11 | year = 1999 | pmid = 10425198 | doi = 10.1006/bbrc.1999.1002 }} and
RANBP9{{cite journal | vauthors = Wang D, Li Z, Messing EM, Wu G | title = Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM | journal = J. Biol. Chem. | volume = 277 | issue = 39 | pages = 36216–22 | year = 2002 | pmid = 12147692 | doi = 10.1074/jbc.M205111200 | doi-access = free }}

References

External links

{{MeshName|Proto-Oncogene+Proteins+c-met}}
[http://www.expasy.org/uniprot/P08581 UniProtKB/Swiss-Prot entry P08581: MET_HUMAN], ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB)
A [http://www.vai.org/met/ table] with references to significant roles of MET in cancer
{{UCSC gene info|MET}}

Category:Tyrosine kinase receptors

Category:EC 2.7.10