c-Met

c-Met
Met proto-oncogene (hepatocyte growth factor receptor)

Crystallographic structure of MET. PDB rendering based on 1r0p.
Identifiers
Symbols MET; AUTS9; HGFR; RCCP2; c-Met
External IDs OMIM: 164860 MGI: 96969 HomoloGene: 206 GeneCards: MET Gene
EC number 2.7.10.1
RNA expression pattern
PBB GE MET 213816 s at tn.png
PBB GE MET 203510 at tn.png
PBB GE MET 211599 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4233 17295
Ensembl ENSG00000105976 ENSMUSG00000009376
UniProt P08581 A1A597
RefSeq (mRNA) NM_000245.2 NM_008591.2
RefSeq (protein) NP_000236.2 NP_032617.2
Location (UCSC) Chr 7:
116.31 – 116.44 Mb		 Chr 6:
17.41 – 17.52 Mb
PubMed search [1] [2]

c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).[1][2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.[3] 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.

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, 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.

Various mutations in the MET gene are associated with papillary renal carcinoma.[4]

Contents

Gene

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


Protein

Schematic structure of MET protein [5]

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.[6]

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.[6]

Intracellular

A Juxtamembrane segment that contains:

  • a serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation[7]
  • a tyrosine (Tyr 1003), which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL[8]
  • 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.[9] The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.[9][10]

MET signaling pathway

MET signaling complex[11]


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 as GRB2, SHC,[12] SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K),[12] or indirectly through the scaffolding protein Gab1[13]

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.[14]

GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity.[15] 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.[16]

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.[17] Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPK activity.[18]
  • 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.[19] 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.[5]
  • 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. [21]
  • The Notch pathway, through transcriptional activation of Delta ligand (see DLL3).[11][22]
Interplay between MET, beta catenin, Wnt, and Notch signaling pathways[11]

Role in development

MET mediates a complex program known as invasive growth.[5] Activation of MET triggers mitogenesis, and morphogenesis.[23]

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).[24] Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others.[25] MET is essential for embryogenesis, because MET -/- mice die in utero due to severe defects in placental development.[26] Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.[5]

Expression

Tissue distribution

MET is normally expressed by epithelial cells.[5] However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, and melanocytes.[23] HGF expression is restricted to cells of mesenchymal origin.[24]

Transcriptional control

MET transcription is activated by HGF and several growth factors.[27] MET promoter has four putative binding sites for Ets, a family of transcription factors that control several invasive growth genes.[27] ETS1 activates MET transcription in vitro.[28] MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen.[29] HIF1 can bind to one of the several hypoxia response elements (HREs) in the MET promoter.[24] Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.[24]

Role in cancer

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

  • 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.[30]

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.[31]

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.[32] 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.[11]

VHL

There is evidence of correlation between inactivation of VHL tumor suppressor gene and increased MET signaling in renal cell carcinoma (RCC).[33]

Cancer therapies targeting HGF/MET

Strategies to inhibit biological activity of MET [5]

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.

  • 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.[34]
  • 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.[35] SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.[36]
  • PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation.[37] Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752.[38]
  • ARQ197 (ArQule) is a promising selective inhibitor of MET, which has entered a phase 2 clinical trial in 2008.
  • 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 (see Poster).
  • SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations. (See Poster.)
  • 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. (See 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 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.[39]
  • 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.[40] 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.[41] 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.[42]

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.[43]

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.[44]

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.[44]

  • 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.[45]
  • OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic[46] and glioblastoma[47] 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.[44]

Interactions

Met has been shown to interact with Hepatocyte growth factor,[48][49] Cbl gene,[50][51] GLMN,[52] CDH1,[53] Grb2[54][55] and RANBP9.[56]

See also

References

  1. ^ Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (February 1991). "Identification of the hepatocyte growth factor receptor as the met proto-oncogene product". Science 251 (4995): 802–4. doi:10.1126/science.1846706. PMID 1846706. 
  2. ^ Galland F, Stefanova M, Lafage M, Birnbaum D (1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15----q23". Cytogenet. Cell Genet. 60 (2): 114–6. doi:10.1159/000133316. PMID 1611909. 
  3. ^ Cooper CS (January 1992). "The met oncogene: from detection by transfection to transmembrane receptor for hepatocyte growth factor". Oncogene 7 (1): 3–7. PMID 1531516. 
  4. ^ "Entrez Gene: MET met proto-oncogene (hepatocyte growth factor receptor)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4233. 
  5. ^ a b c d e f Gentile A, Trusolino L, Comoglio PM (March 2008). "The Met tyrosine kinase receptor in development and cancer". Cancer Metastasis Rev. 27 (1): 85–94. doi:10.1007/s10555-007-9107-6. PMID 18175071. 
  6. ^ a b Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (December 2003). "Met, metastasis, motility and more". Nat. Rev. Mol. Cell Biol. 4 (12): 915–25. doi:10.1038/nrm1261. PMID 14685170. 
  7. ^ Gandino L, Longati P, Medico E, Prat M, Comoglio PM (January 1994). "Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase". J. Biol. Chem. 269 (3): 1815–20. PMID 8294430. 
  8. ^ Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M (November 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. doi:10.1016/S1097-2765(01)00378-1. PMID 11741535. 
  9. ^ a b Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM (April 1994). "A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family". Cell 77 (2): 261–71. doi:10.1016/0092-8674(94)90318-2. PMID 7513258. 
  10. ^ Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C (November 1996). "Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development". Cell 87 (3): 531–42. doi:10.1016/S0092-8674(00)81372-0. PMID 8898205. 
  11. ^ a b c d Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J (December 2004). "Regulation of c-Met-dependent gene expression by PTEN". Oncogene 23 (57): 9173–82. doi:10.1038/sj.onc.1208146. PMID 15516982. 
  12. ^ a b Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG (April 1995). "The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein". Oncogene 10 (8): 1631–8. PMID 7731718. 
  13. ^ Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W (November 1996). "Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis". Nature 384 (6605): 173–6. doi:10.1038/384173a0. PMID 8906793. 
  14. ^ Furge KA, Zhang YW, Vande Woude GF (November 2000). "Met receptor tyrosine kinase: enhanced signaling through adapter proteins". Oncogene 19 (49): 5582–9. doi:10.1038/sj.onc.1203859. PMID 11114738. 
  15. ^ Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM (January 2001). "Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling". Oncogene 20 (2): 156–66. doi:10.1038/sj.onc.1204047. PMID 11313945. 
  16. ^ Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM (March 2000). "Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis". Oncogene 19 (12): 1509–18. doi:10.1038/sj.onc.1203514. PMID 10734310. 
  17. ^ O'Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE (July 2004). "ERK and MMPs sequentially regulate distinct stages of epithelial tubule development". Dev. Cell 7 (1): 21–32. doi:10.1016/j.devcel.2004.06.001. PMID 15239951. 
  18. ^ Marshall CJ (January 1995). "Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation". Cell 80 (2): 179–85. doi:10.1016/0092-8674(95)90401-8. PMID 7834738. 
  19. ^ Graziani A, Gramaglia D, Cantley LC, Comoglio PM (November 1991). "The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase". J. Biol. Chem. 266 (33): 22087–90. PMID 1718989. 
  20. ^ Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM (January 1998). "Induction of epithelial tubules by growth factor HGF depends on the STAT pathway". Nature 391 (6664): 285–8. doi:10.1038/34657. PMID 9440692. 
  21. ^ Monga SP, Mars WM, Pediaditakis P, Bell A, Mulé K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK (April 2002). "Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes". Cancer Res 7 (62): 2064–71. ISSN 0008-5472. PMID 11929826. 
  22. ^ Gude NA, Emmanuel G, Wu W, Cottage CT, Fischer K, Quijada P, Muraski JA, Alvarez R, Rubio M, Schaefer E, Sussman MA (May 2008). "Activation of Notch-mediated protective signaling in the myocardium". Circ. Res. 102 (9): 1025–35. doi:10.1161/CIRCRESAHA.107.164749. PMID 18369158. 
  23. ^ a b "he fields of HGF/c-Met involvement". HealthValue. http://www.healthvalue.net/cmetfields.html. Retrieved 2009-06-13. 
  24. ^ a b c d Boccaccio C, Comoglio PM (August 2006). "Invasive growth: a MET-driven genetic programme for cancer and stem cells". Nat. Rev. Cancer 6 (8): 637–45. doi:10.1038/nrc1912. PMID 16862193. 
  25. ^ Birchmeier C, Gherardi E (October 1998). "Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase". Trends Cell Biol. 8 (10): 404–10. doi:10.1016/S0962-8924(98)01359-2. PMID 9789329. 
  26. ^ Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N (February 1995). "Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor". Nature 373 (6516): 702–5. doi:10.1038/373702a0. PMID 7854453. 
  27. ^ a b Shirasaki F, Makhluf HA, LeRoy C, Watson DK, Trojanowska M (December 1999). "Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter". Oncogene 18 (54): 7755–64. doi:10.1038/sj.onc.1203360. PMID 10618716. 
  28. ^ Gambarotta G, Boccaccio C, Giordano S, Andŏ M, Stella MC, Comoglio PM (November 1996). "Ets up-regulates MET transcription". Oncogene 13 (9): 1911–7. PMID 8934537. 
  29. ^ Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (April 2003). "Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene". Cancer Cell 3 (4): 347–61. doi:10.1016/S1535-6108(03)00085-0. PMID 12726861. 
  30. ^ "HGF/c-Met and cancer". HealthValue. http://www.healthvalue.net/c-metandcancer.html. Retrieved 2009-06-13. 
  31. ^ Kim S, Lee UJ, Kim MN, et al. (June 2008). "MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2)". J. Biol. Chem. 283 (26): 18158–66. doi:10.1074/jbc.M800186200. PMID 18456660. 
  32. ^ Maehama T, Dixon JE (May 1998). "The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate". J. Biol. Chem. 273 (22): 13375–8. doi:10.1074/jbc.273.22.13375. PMID 9593664. 
  33. ^ Morris MR, Gentle D, Abdulrahman M, Maina EN, Gupta K, Banks RE, Wiesener MS, Kishida T, Yao M, Teh B, Latif F, Maher ER (June 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 Res. 65 (11): 4598–606. doi:10.1158/0008-5472.CAN-04-3371. PMID 15930277. 
  34. ^ Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C (July 2002). "K252a inhibits the oncogenic properties of Met, the HGF receptor". Oncogene 21 (32): 4885–93. doi:10.1038/sj.onc.1205622. PMID 12118367. 
  35. ^ 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 (July 2004). "The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants". Oncogene 23 (31): 5387–93. doi:10.1038/sj.onc.1207691. PMID 15064724. 
  36. ^ 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 (November 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". Mol. Cancer Ther. 2 (11): 1085–92. PMID 14617781. 
  37. ^ 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 (November 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 Res. 63 (21): 7345–55. PMID 14612533. 
  38. ^ 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 (February 2006). "Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752". Proc. Natl. Acad. Sci. U.S.A. 103 (7): 2316–21. doi:10.1073/pnas.0508776103. PMC 1413705. PMID 16461907. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1413705. 
  39. ^ Matsumoto K, Nakamura T (April 2003). "NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics". Cancer Sci. 94 (4): 321–7. doi:10.1111/j.1349-7006.2003.tb01440.x. PMID 12824898. 
  40. ^ Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF (June 2001). "Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models". Proc. Natl. Acad. Sci. U.S.A. 98 (13): 7443–8. doi:10.1073/pnas.131200498. PMC 34688. PMID 11416216. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=34688. 
  41. ^ 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 (February 2006). "Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors". Cancer Res. 66 (3): 1721–9. doi:10.1158/0008-5472.CAN-05-3329. PMID 16452232. 
  42. ^ Mazzone M, Basilico C, Cavassa S, Pennacchietti S, Risio M, Naldini L, Comoglio PM, Michieli P (November 2004). "An uncleavable form of pro–scatter factor suppresses tumor growth and dissemination in mice". J. Clin. Invest. 114 (10): 1418–32. doi:10.1172/JCI22235. PMC 525743. PMID 15545993. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=525743. 
  43. ^ Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, Comoglio PM (July 2004). "Targeting the tumor and its microenvironment by a dual-function decoy Met receptor". Cancer Cell 6 (1): 61–73. doi:10.1016/j.ccr.2004.05.032. PMID 15261142. 
  44. ^ a b c Reang P, Gupta M, Kohli K (2006). "Biological Response Modifiers in Cancer". MedGenMed 8 (4): 33. PMC 1868326. PMID 17415315. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1868326. 
  45. ^ Petrelli A, Circosta P, Granziero L, Mazzone M, Pisacane A, Fenoglio S, Comoglio PM, Giordano S (March 2006). "Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity". Proc. Natl. Acad. Sci. U.S.A. 103 (13): 5090–5. doi:10.1073/pnas.0508156103. PMC 1458799. PMID 16547140. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1458799. 
  46. ^ 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 (June 2008). "MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival". Cancer Res. 68 (11): 4360–8. doi:10.1158/0008-5472.CAN-07-5960. PMID 18519697. 
  47. ^ Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K (October 2006). "A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo". Clin. Cancer Res. 12 (20 Pt 1): 6144–52. doi:10.1158/1078-0432.CCR-05-1418. PMID 17062691. 
  48. ^ Comoglio, P M (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS (SWITZERLAND) 65: 131–65. ISSN 1023-294X. PMID 8380735. 
  49. ^ Naldini, L; Weidner K M, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan R P, Hartmann G, Zarnegar R, Michalopoulos G K (Oct. 1991). "Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor". EMBO J. (ENGLAND) 10 (10): 2867–78. ISSN 0261-4189. PMC 452997. PMID 1655405. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=452997. 
  50. ^ Petrelli, Annalisa; Gilestro Giorgio F, Lanzardo Stefania, Comoglio Paolo M, Migone Nicola, Giordano Silvia (Mar. 2002). "The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met". Nature (England) 416 (6877): 187–90. doi:10.1038/416187a. ISSN 0028-0836. PMID 11894096. 
  51. ^ Ng, Cherlyn; Jackson Rebecca A, Buschdorf Jan P, Sun Qingxiang, Guy Graeme R, Sivaraman J (Mar. 2008). "Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates". EMBO J. (England) 27 (5): 804–16. doi:10.1038/emboj.2008.18. PMC 2265755. PMID 18273061. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2265755. 
  52. ^ Grisendi, S; Chambraud B, Gout I, Comoglio P M, Crepaldi T (Dec. 2001). "Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor". J. Biol. Chem. (United States) 276 (49): 46632–8. doi:10.1074/jbc.M104323200. ISSN 0021-9258. PMID 11571281. 
  53. ^ Davies, G; Jiang W G, Mason M D (Apr. 2001). "HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells". Int. J. Mol. Med. (Greece) 7 (4): 385–8. ISSN 1107-3756. PMID 11254878. 
  54. ^ Ponzetto, C; Zhen Z, Audero E, Maina F, Bardelli A, Basile M L, Giordano S, Narsimhan R, Comoglio P (Jun. 1996). "Specific uncoupling of GRB2 from the Met receptor. Differential effects on transformation and motility". J. Biol. Chem. (UNITED STATES) 271 (24): 14119–23. doi:10.1074/jbc.271.24.14119. ISSN 0021-9258. PMID 8662889. 
  55. ^ Liang, Q; Mohan R R, Chen L, Wilson S E (Jul. 1998). "Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways". Invest. Ophthalmol. Vis. Sci. (UNITED STATES) 39 (8): 1329–38. ISSN 0146-0404. PMID 9660480. 
  56. ^ Wang, Dakun; Li Zaibo, Messing Edward M, Wu Guan (Sep. 2002). "Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM". J. Biol. Chem. (United States) 277 (39): 36216–22. doi:10.1074/jbc.M205111200. ISSN 0021-9258. PMID 12147692. 

Further reading

  • Peruzzi B, Bottaro DP (2006). "Targeting the c-Met signaling pathway in cancer". Clin. Cancer Res. 12 (12): 3657–60. doi:10.1158/1078-0432.CCR-06-0818. PMID 16778093. 
  • Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (December 2003). "Met, metastasis, motility and more". Nat. Rev. Mol. Cell Biol. 4 (12): 915–25. doi:10.1038/nrm1261. PMID 14685170. 
  • Zhang YW, Vande Woude GF (February 2003). "HGF/SF-met signaling in the control of branching morphogenesis and invasion". J. Cell. Biochem. 88 (2): 408–17. doi:10.1002/jcb.10358. PMID 12520544. 
  • Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V, Tulashe D, Reveneau S (April 2002). "Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway". Oncogene 21 (15): 2309–19. doi:10.1038/sj.onc.1205297. PMID 11948414. 
  • Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS 65: 131–65. PMID 8380735. 
  • Maulik G, Shrikhande A, Kijima T, et al. (2002). "Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition". Cytokine Growth Factor Rev. 13 (1): 41–59. doi:10.1016/S1359-6101(01)00029-6. PMID 11750879. 
  • Ma PC, Maulik G, Christensen J, Salgia R (2004). "c-Met: structure, functions and potential for therapeutic inhibition". Cancer Metastasis Rev. 22 (4): 309–25. doi:10.1023/A:1023768811842. PMID 12884908. 
  • Knudsen BS, Edlund M (2004). "Prostate cancer and the met hepatocyte growth factor receptor". Adv. Cancer Res.. Advances in Cancer Research 91: 31–67. doi:10.1016/S0065-230X(04)91002-0. ISBN 978-0-12-006691-9. PMID 15327888. 
  • Dharmawardana PG, Giubellino A, Bottaro DP (2005). "Hereditary papillary renal carcinoma type I". Curr. Mol. Med. 4 (8): 855–68. doi:10.2174/1566524043359674. PMID 15579033. 
  • Kemp LE, Mulloy B, Gherardi E (2006). "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors". Biochem. Soc. Trans. 34 (Pt 3): 414–7. doi:10.1042/BST0340414. PMID 16709175. 

External links

  • A table with references to significant roles of MET in cancer.
v · d · eNeoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes
Ligand
ONCO: c-Sis/PDGF · HGF
Receptor
TSP: CDH1
TSP: PTCH1
ONCO: ErbB/c-ErbB (HER2/neu, Her 3) - c-Met - c-Ret
ONCO: c-Kit - Flt3
Intracellular signaling P+Ps
ONCO: Beta-catenin · TSP: APC
TSP: SMAD2, SMAD4
TSP: PTEN · ONCO: c-Akt
Hippo signaling pathway
Other/unknown
TSP: Maspin · ONCO: c-Src
Nucleus
TSP: p53 · pRb · WT1 · p16/p14arf · ONCO: CDK4 · Cyclin D · Cyclin E
ONCO: BRCA1 - BRCA2
TSP: VHL  · ONCO: CBL - MDM2
TSP: KLF6  · ONCO: AP-1 (c-Fos, c-Jun) - c-Myc
Mitochondria
Other/ungrouped
c-Bcl-2 - Notch - Stathmin

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)
v · d · eReceptors: growth factor receptors
Type I cytokine receptor
Receptor protein serine/threonine kinase
Receptor tyrosine kinase
Tumor necrosis factor receptor
Ig superfamily
Other/ungrouped
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

http://www.thechangeblog.com/dont-think-about-it/


Wikimedia Foundation. 2010.

Игры ⚽ Поможем написать курсовую

Look at other dictionaries:

  • met — met·ri·cal; met·ri·cism; met·ri·cist; met·ri·fi·ca·tion; met·ri·fy; met·rio·cra·nic; met·rio·metopic; met·ro·logical; met·ro·mania; met·ron; met·ro·nome; met·ro·nom·ic; met·ro·pole; met·ro·pol·i·tan·ate; met·ro·pol·i·tan·ism;… …   English syllables

  • Met — Met, auch Honigwein genannt, ist ein alkoholisches Getränk aus Honig und Wasser. Teilweise werden auch, besonders in der privaten Produktion, verschiedene Gewürze, Früchte und Fruchtsäfte (zumeist Äpfel und Apfelsaft) zugegeben oder anstelle des… …   Deutsch Wikipedia

  • Met — or MET or The Met may refer to: Contents 1 In the arts 2 In computing and the Internet 3 In medicine and physiology 4 In public safety …   Wikipedia

  • Met-Rx — is a brand name of nutritional supplements, originally produced by Met Rx, Inc., a California company started by A. Scott Connelly, and sold several times since. The brand is best known as the product to pioneer a new category of bodybuilding… …   Wikipedia

  • Met Éireann — Meteorological Service overview Formed 1936 (1936) Preceding Meteorological Service British Meteorological Office (Before Independence) …   Wikipedia

  • Met 3 — site in March 2011 General information Status On hold Type Resid …   Wikipedia

  • Met (Begriffsklärung) — Met bezeichnet: ein alkoholisches Getränk, siehe Met Met steht als Abkürzung oder Kurzform für: Metropolitan Police Service, Londoner Polizei Metropolitan Opera, ein Opernhaus in New York City Metropolitan Museum of Art in New York City Methionin …   Deutsch Wikipedia

  • Met Film School — Established 2003 (2003) Type Open Director Jonny Persey Location London, United Kingdom …   Wikipedia

  • Met Center — Former names Metropolitan Sports Center (1967 1982) Location Bloomington, Minnesota …   Wikipedia

  • mét- — mét(a) ♦ Élément, du gr. meta, exprimant la succession, le changement, la participation, et en philosophie et dans les sciences humaines « ce qui dépasse, englobe » (un objet, une science) : métalangage, métamathématique. ⇒MÉT(A) , (MÉT , MÉTA… …   Encyclopédie Universelle

  • Met Office — Créée le 1854 Juridiction Royaume Uni Siège Exeter Ministre responsable …   Wikipédia en Français

Share the article and excerpts

Direct link
… Do a right-click on the link above
and select “Copy Link”