- C-Met
"MET" (mesenchymal-epithelial transition factor) is a
proto-oncogene that encodes a protein MET, also known as c-Met or hepatocyte growth factor receptor (HGFR). MET is a membrane receptor that is essential for embryonic development and wound healing.Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth. Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis ) that supply the tumor with nutrients, and cancer spread to other organs (metastasis ). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, 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. PBB_Summary
section_title =
summary_text = The proto-oncogene MET product is the hepatocyte growth factor receptor and encodes tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. 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 = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4233| accessdate = ]"MET" Gene
"MET" proto-oncogene ( [http://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. "MET" is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.
MET Protein
MET is a
receptor tyrosine kinase (RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at a furin site to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by a disulfide bridge. Birchmeier, C., Birchmeier, W., Gherardi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. "Nature Reviews. Molecular Cell Biology", 4: 915–925. [http://www.ncbi.nlm.nih.gov/pubmed/14685170?dopt=Abstract PMID: 14685170] ] Extracellular Portion:
# 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 immunoglobuline-like structures (Ig domains), a typical protein-protein interaction region. Intracellular Portion:
# Juxtamembrane segment that contains:
#* a serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation [ Gandino L, Longati P, Medico E, Prat M, Comoglio PM. 1994. Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. "J Biol Chem", 269(3):1815-20. [http://www.ncbi.nlm.nih.gov/pubmed/8294430?ordinalpos=91&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 8294430] ] ;
#* a tyrosine (Tyr 1003), which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL [ Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M. (2001). Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. "Mol Cell", 8(5): 995-1004. [http://www.ncbi.nlm.nih.gov/pubmed/11741535?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 11741535] ] ;
# 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. [ Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM. (1994). A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. "Cell", 77: 261-271. [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pubmed&doptcmdl=citation&term=CELL%5Bta%5D%20AND%2077%5Bvi%5D%20AND%20261%5Bpg%5D PMID 7513258] ] The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both "in vitro" Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C. (1996). Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. "Cell", 87: 531–542. [http://www.ncbi.nlm.nih.gov/pubmed/8898205?dopt=AbstractPMID: 8898205] ] and "in vivo" [ Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM. (1994). A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. "Cell", 77: 261–271. [http://www.ncbi.nlm.nih.gov/pubmed/7513258?dopt=Abstract PMID: 7513258] ] .MET Signaling Pathway
[
Human MET signaling pathway, according to the Cancer Genome Anatomy Project [http://cgap.nci.nih.gov/Pathways/BioCarta/h_metPathway (CGAP)] ] MET activation by its ligand
HGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively knows as the invasive growth program. The transducers interact with the intracellular multisubstrate docking site of MET either directly, such asGRB2 ,SHC [ Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG, et al. (1995). The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. "Oncogene", 10: 1631–1638. [http://www.ncbi.nlm.nih.gov/pubmed/7731718?dopt=Abstract PMID: 7731718] ] ,SRC , and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K ) , or indirectly through the scaffolding protein Gab1 [ Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W. (1996). Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. "Nature", 384: 173–176. [http://www.ncbi.nlm.nih.gov/pubmed/8906793?dopt=Abstract PMID: 8906793] ] . 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 [ Furge KA, Zhang YW, Vande Woude GF. (2000). Met receptor tyrosine kinase: Enhanced signaling through adapter proteins. "Oncogene", 19: 5582–5589. [http://www.ncbi.nlm.nih.gov/pubmed/11114738?dopt=Abstract PMID: 11114738] ] . GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity [ Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM. (2001). Gab1 phosphorylation: A novel mechanism for negative regulation of HGF receptor signaling. "Oncogene", 20: 156–166. [http://www.ncbi.nlm.nih.gov/pubmed/11313945?dopt=Abstract PMID: 11313945] ] . 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 [ Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM. (2000). Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. "Oncogene", 19: 1509–1518. [http://www.ncbi.nlm.nih.gov/pubmed/10734310?dopt=Abstract PMID: 10734310] ] .MET engagement activates multiple
signal transduction pathways :
# TheRAS pathway mediates HGF-inducedscattering andproliferation signals, which lead tobranching morphogenesis [ O'Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE. (2004). ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. "Developments in Cell", 7: 21–32. [http://www.ncbi.nlm.nih.gov/pubmed/15239951?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 15239951] ] . Of note, HGF, differently from mostmitogens , induces sustained RAS activation, and thus prolongedMAPK activity [ Marshall, C J (1995). Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. "Cell", 80: 179–185. [http://www.ncbi.nlm.nih.gov/pubmed/7834738?dopt=Abstract PMID: 7834738] ] .
# ThePI3K pathway is activated in two ways: PI3K can be either downstream ofRAS , or it can be recruited directly through the multifunctional docking site [ Graziani A, Gramaglia D, Cantley LC, Comoglio PM.. (1991). The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. Journal of Biological Chemistry, 266, 22087–22090. [http://www.ncbi.nlm.nih.gov/pubmed/1718989?dopt=Abstract PMID: 1718989] ] . 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 Gentile A, Trusolino L, Comoglio PM. (2008). The Met tyrosine kinase receptor in development and cancer. "Cancer Metastasis Reviews", 27(1):85-94. [http://www.ncbi.nlm.nih.gov/pubmed/18175071?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 18175071] ] .
# TheSTAT pathway, together with the sustained MAPK activation, is necessary for the HGF-inducedbranching morphogenesis . MET activates theSTAT3 transcription factor directly, through anSH2 domain [ Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM. (1998). Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. "Nature", 391: 285–288. [http://www.ncbi.nlm.nih.gov/pubmed/9440692?dopt=Abstract PMID: 9440692] ] .
# 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 [ [http://www.healthvalue.net/wntpathways.html Health Value: Interplay between Wnt and MET signaling pathways.] ] .
# TheNotch pathway, through transcriptional activation ofDelta ligand [ Gude NA, Emmanuel G, Wu W, Cottage CT, Fischer K, Quijada P, Muraski JA, Alvarez R, Rubio M, Schaefer E, Sussman MA. (2008). Activation of Notch-mediated protective signaling in the myocardium. "Circulation Research", 102(9): 1025-35. [http://www.ncbi.nlm.nih.gov/pubmed/18369158?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 18369158] ] .Essential Role in Development
MET mediates a complex program known as invasive growth Gentile A, Trusolino L, Comoglio PM. (2008). The Met tyrosine kinase receptor in development and cancer. "Cancer Metastasis Reviews", 27(1):85-94. [http://www.ncbi.nlm.nih.gov/pubmed/18175071?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 18175071] ] . Activation of MET triggers
mitogenesis , andmorphogenesis [ [http://www.healthvalue.net/cmetfields.html Health Value: Biological activity of MET] ] . Duringembryonic development , transformation of the flat, two-layergerminal disc into a three-dimensional body depends on transition of some cells from anepithelial phenotype to spindle-shaped cells with motile behaviour, amesenchymal phenotype . This process is referred to asepithelial-mesenchymal transition (EMT). Boccaccio C, Comoglio PM. (2006). Invasive growth: a MET-driven genetic programme for cancer and stem cells. "Nat Rev Cancer", 6(8): 637-45. [http://www.ncbi.nlm.nih.gov/pubmed/16862193?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 16862193] ] Later in embryonic development, MET is crucial forgastrulation ,angiogenesis ,myoblast migration,bone remodeling , andnerve sprouting among others [ Birchmeier C and Gherardi E. (1998). Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. "Trends in Cell Biology", 8(10):404-10. [http://www.ncbi.nlm.nih.gov/sites/entrez PMID: 9789329] ] . MET is essential forembryogenesis , because "MET" -/- mice die "in utero" due to severe defects in placental development [ Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N. (1995). Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. "Nature", 373: 702–705. [http://www.ncbi.nlm.nih.gov/pubmed/7854453?dopt=Abstract PMID: 7854453] ] . Furthermore, MET is required for such critical processes asliver regeneration andwound healing during adulthood .Expression of HGF and MET
Location
MET is normally expressed by
epithelial cells . However, MET is also found onendothelial cells ,neurons ,hepatocytes ,hematopoietic cells, andmelanocytes [ [http://www.healthvalue.net/cmetfields.html Health Value: MET expression.] ] . HGF expression is restricted to cells ofmesenchymal origin .Transcriptional Control
"MET" transcription is activated by HGF and several
growth factors Shirasaki F, Makhluf HA, LeRoy C, Watson DK, Trojanowska M. (1999). Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter. "Oncogene", 18: 7755–7764. [http://www.ncbi.nlm.nih.gov/pubmed/10618716?dopt=Abstract PMID: 10618716] ] .Ets1
"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" [ Gambarotta G, Boccaccio C, Giordano S, Andŏ M, Stella MC, Comoglio PM. (1996). Ets up-regulates MET transcription. "Oncogene", 13: 1911–1917. [http://www.ncbi.nlm.nih.gov/pubmed/8934537?dopt=Abstract PMID: 8934537] ] .HIF1
"MET" transcription is activated by
hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen [ Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. (2003). Hypoxia promotes invasive growth by transcriptional activation of the Met protooncogene. "Cancer Cell", 3, 347–361. [http://www.ncbi.nlm.nih.gov/pubmed/12726861?dopt=Abstract PMID: 12726861] ] . HIF1 can bind to one of the severalhypoxia response elements (HREs) in the "MET" promoter .AP-1
Hypoxia also activates transcription factor AP-1, which is involved in "MET" transcription .
Central 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 tometalloprotease production), which often leads tometastasis [ [http://www.healthvalue.net/c-metandcancer.html Health Value: Role of MET in cancer.] ] .MET and Tumour Suppresor Genes
"PTEN"
"
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 [ Leslie NR, Bennett D, Gray A, Pass I, Hoang-Xuan K and Downes CP. (2001). Biochem. J., 357, 427–435. [http://www.ncbi.nlm.nih.gov/pubmed/9593664?dopt=Abstract&holding=npg PMID: 9593664] ] . 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. Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J. (2004). Regulation of c-Met-dependent gene expression by PTEN. "Oncogene", 23(57): 9173-82. [http://www.ncbi.nlm.nih.gov/pubmed/15516982?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 15516982] ]"VHL"
There is evidence of correlation between inactivation of "
VHL "tumor suppressor gene and increased MET signaling inrenal cell carcinoma (RCC) [ Morris MR, Gentle D, Abdulrahman M, Maina EN, Gupta K, Banks RE, Wiesener MS, Kishida T, Yao M, Teh B, Latif F, Maher ER. (2005). Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. "Cancer Research", 65(11): 4598-606. [http://www.ncbi.nlm.nih.gov/pubmed/15930277?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 15930277] ] .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.
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.
# [http://www.fermentek.co.il/K252a.htm K252a] (Fermentek Biotechnology) is astaurosporine analogue isolated from "Nocardiopsis" sp. soilfungi , and it is a potent inhibitor of allreceptor tyrosine kinases (RTKs). At nanomolar concentrations, K252a inhibits both thewild type and the mutant (M1268T) MET function. [ Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C. (2002). K252a inhibits the oncogenic properties of Met, the HGF receptor. "Oncogene", 21: 4885–4893. [http://www.ncbi.nlm.nih.gov/pubmed/12118367?dopt=Abstract PMID: 12118367] ]
#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 [ 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. (2004). The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene, 23, 5387–5393. [http://www.ncbi.nlm.nih.gov/pubmed/15064724?dopt=Abstract PMID: 15064724] ] . SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells [ Xueyan Wang, Phuong Le, Congxin Liang, Julie Chan, David Kiewlich, Todd Miller, Dave Harris, Li Sun, Audie Rice, Stefan Vasile, Robert A. Blake, Anthony R. Howlett, Neela Patel, Gerald McMahon and Kenneth E. Lipson. (2003). 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. "Molecular Cancer Therapy", 2: 1085-1092. [http://www.ncbi.nlm.nih.gov/pubmed/14617781?dopt=Abstract PMID: 14617781] ] .
#PHA-665752 (Pfizer ) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation [ 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. (2003). A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes "in vitro" and exhibits cytoreductive antitumor activity "in vivo". "Cancer Research", 63: 7345–7355. [http://www.ncbi.nlm.nih.gov/pubmed/14612533?dopt=Abstract PMID: 14612533] ] . Furthermore, some tumors harboring "MET" amplifications are highly sensitive to treatment with PHA-665752 [ 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. (2006). Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of the United States of America, 103, 2316–2321. [http://www.ncbi.nlm.nih.gov/pubmed/16461907?dopt=Abstract PMID: 16461907] ] .
# [http://www.arqule.com/res/onc ARQ197] (ArQule) is a promising selective inhibitor of MET, which has entered a phase 2 clinical trial in 2008.
# [http://www.exelixis.com/pipeline_xl880.shtml XL880] (Exelixis) targets multiplereceptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of XL880 are MET,VEGFR2 , andKDR . XL880 has completed a phase 2 clinical trials with indications for papillaryrenal cell carcinoma ,gastric cancer , andhead and neck cancer (see [http://www.exelixis.com/eortc/posters/AACR_NCI_EORTC2007_XL880_phase2.pdf Poster] ).
#SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations. (See [http://www.sgxpharma.com/pipeline/documents/SGX523METAACR07.pdf Poster] .)
#MP470 (SuperGen) is a novel inhibitor ofc-KIT , MET,PDGFR , Flt3, andAXL . Phase I clinical trial of MP470 had been announced in 2007. (See [http://www.supergen.com/subpages/pdf/pipeline/MP470_5421v2lr_synergybiomarkers.pdf Poster] .)HGF Inhibitors
Since HGF is the only known ligand of MET, formation of a HGF:MET complex blocks MET
biological activity . For this purpose, truncated HGF, anti-HGF neutralizing antibodies, and an uncleavable form of HGF have been utilized so far. The major limitation of HGF inhibitors is that they block only HGF-dependent MET activation.
#NK4 competes with HGF as it binds MET without inducing receptor activation, thus behaving as a fullantagonist . 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. [ Matsumoto K, Nakamura T. (2003). NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. "Cancer Science", 94: 321–327. [http://www.ncbi.nlm.nih.gov/pubmed/12824898?dopt=Abstract PMID: 12824898] ]
#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 [ Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF. (2001). Neutralizingmonoclonal antibodies to HGF show antitumor activity inxenografts . "Proceedings of the National Academy of Sciences of the United States of America", 98: 7443–7448. [http://www.ncbi.nlm.nih.gov/pubmed/11416216?dopt=Abstract PMID: 11416216] ] . 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 [ 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. (2006). Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. "Cancer Research", 66: 1721–1729. [http://www.ncbi.nlm.nih.gov/pubmed/16452232?dopt=Abstract PMID: 16452232] ] . 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 . [ Mazzone M, Basilico C, Cavassa S, Pennacchietti S, Risio M, Naldini L, Comoglio PM, Michieli P. (2004). An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. "Journal of Clinical Investigation", 114: 1418–1432. [http://www.ncbi.nlm.nih.gov/pubmed/15545993?dopt=Abstract PMID: 15545993] ]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. [ Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, Comoglio PM. (2004). Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. "Cancer Cell", 6: 61–73. [http://www.ncbi.nlm.nih.gov/pubmed/15261142?dopt=Abstract PMID: 15261142] ]Immunotherapy Targeting MET
Drugs used for
immunotherapy 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 Reang P, Gupta M, Kohli K. (2006). Biological response modifiers in cancer. "Medscape General Medicine", 8(4): 33. [http://www.ncbi.nlm.nih.gov/pubmed/17415315?ordinalpos=26&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 17415315] ] .*Passive Immunotherapy:Administering
monoclonal 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. :# DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces both shedding 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. [ Petrelli A, Circosta P, Granziero L, Mazzone M, Pisacane A, Fenoglio S, Comoglio PM, Giordano S. (2006). Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. "Proceedings of the National Academy of Sciences of the United States of America", 103: 5090–5095. [http://www.ncbi.nlm.nih.gov/pubmed/16547140?dopt=Abstract PMID: 16547140] ] :# OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic [ 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. (2008). MetMAb, the One-Armed 5D5 Anti-c-Met Antibody, Inhibits Orthotopic Pancreatic Tumor Growth and Improves Survival. "Cancer Research", 68(11): 4360-4368. [http://www.ncbi.nlm.nih.gov/pubmed/18519697?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 18519697] ] and glioblastoma [ Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K. (2006). A novel one-armed anti-c-Met antibody inhibits glioblastoma growth "in vivo". "Clinical Cancer Research", 12(20): 6144-52. [http://www.ncbi.nlm.nih.gov/pubmed/17062691?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID: 17062691] ] 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 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 byFDA for the treatment ofrenal cell carcinoma and metastatic melanoma, which often have deregulated MET activity.External links
*
* [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).
*Tpr-met fusion protein References
Further reading
*
* Birchmeier, C., Birchmeier, W., Gheradi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. "Nature Reviews Molecular Cell Biology, 4," 915—925. PMID 14685170 [http://dx.doi.org/10.1038/nrm1261 doi:10.1038/nrm1261]
* Zhang, Y., & Vande Woude, G. F. (2003). HGF/SF-Met signaling in the control of branching morphogenesis and invasion. "Journal of Cellular Biochemistry, 88," 408—417. PMID 12520544 [http://dx.doi.org/10.1002/jcb.10358 doi:10.1002/jcb.10358]
* Paumelle, R., Tulashe, D., Kherrouche, Z., Plaza, S., Leroy, C., Reveneau, S., Vandenbunder, B., & Fafeur, V. (2002). Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. "Oncogene, 21," 2309—2319. PMID 11948414 [http://dx.doi.org/10.1038/sj.onc.1205297 doi:10.1038/sj.onc.1205297] PBB_Further_reading
citations =
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