c-Met

MET proto-oncogene, receptor tyrosine kinase

Crystallographic structure of MET. PDB rendering based on 1r0p.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MET ; AUTS9; DFNB97; HGFR; RCCP2; c-Met
External IDs OMIM: 164860 MGI: 96969 HomoloGene: 206 ChEMBL: 3717 GeneCards: MET Gene
EC number 2.7.10.1
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 4233 17295
Ensembl ENSG00000105976 ENSMUSG00000009376
UniProt P08581 n/a
RefSeq (mRNA) NM_000245 NM_008591
RefSeq (protein) NP_000236 NP_032617
Location (UCSC) Chr 7:
116.67 – 116.8 Mb		 Chr 6:
17.46 – 17.57 Mb
PubMed search

c-Met, also called MET or hepatocyte growth factor receptor (HGFR),[1][2] is a protein that in humans is encoded by the MET gene (MET proto-oncogene, receptor tyrosine kinase), which earlier in the discovery process had also been called MNNG HOS transforming gene. The 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 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 ligand of the MET receptor. 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.

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.[4][5]

Various mutations in the MET gene are associated with papillary renal carcinoma.[6]

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 [7]

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.[8]

Extracellular

Intracellular

A Juxtamembrane segment that contains:

MET signaling pathway

MET signaling complex[13]


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,[14] 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,[15] SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K),[15] or indirectly through the scaffolding protein Gab1[16]

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.[17]

GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity.[18] 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.[19]

Activation of signal transduction

MET engagement activates multiple signal transduction pathways:

Interplay between MET, beta catenin, Wnt, and Notch signaling pathways[13]

Role in development

MET mediates a complex program known as invasive growth.[7] Activation of MET triggers mitogenesis, and morphogenesis.[26][27]

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).[28] Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others.[29] MET is essential for embryogenesis, because MET −/− mice die in utero due to severe defects in placental development.[30] Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.[7]

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.[31] 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.[32] However, MET is not essential for heart development, since α-MHCMet-KO mice show normal heart development.[33]

Expression

Tissue distribution

MET is normally expressed by epithelial cells.[7] However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, melanocytes and neonatal cardiomyocytes.[27][34] HGF expression is restricted to cells of mesenchymal origin.[28]

Transcriptional control

MET transcription is activated by HGF and several growth factors.[35] MET promoter has four putative binding sites for Ets, a family of transcription factors that control several invasive growth genes.[35] ETS1 activates MET transcription in vitro.[36] MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen.[37] HIF1 can bind to one of the several hypoxia response elements (HREs) in the MET promoter.[28] Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.[28]

Clinical significance

Role in cancer

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

Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.[39]

MET amplification has emerged as a potential biomarker of the clear cell tumor subtype.[40]

The amplification of the cell surface receptor MET often drives resistance to anti-EGFR therapies in colorectal cancer.[41]

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.[42] 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.[43] A rare mutation that appears in two family members, one with autism and the other with a social and communication disorder.[44] 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[45][46][47][48][49] and can impact the development and function of circuits involved in social and emotional behavior.[50]

Role in heart function

In adult mice, MET is required to protect cardiomyocytes by preventing age-related oxidative stress, apoptosis, fibrosis and cardiac dysfunction.[33] 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.[51][52]

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.[53][54]

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.[55] 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.[13]

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.[56][57]

Cancer therapies targeting HGF/MET

Strategies to inhibit biological activity of MET [7]

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 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.

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.

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.[68]

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.[69]

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.[69]

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.[69]

Interactions

Met has been shown to interact with:

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 c-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. ↑ Johnson M, Koukoulis G, Kochhar K, Kubo C, Nakamura T, Iyer A (Sep 1995). "Selective tumorigenesis in non-parenchymal liver epithelial cell lines by hepatocyte growth factor transfection". Cancer Letters 96 (1): 37–48. doi:10.1016/0304-3835(95)03915-j. PMID 7553606.
  5. ↑ Kochhar KS, Johnson ME, Volpert O, Iyer AP (1995). "Evidence for autocrine basis of transformation in NIH-3T3 cells transfected with met/HGF receptor gene". Growth Factors 12 (4): 303–13. doi:10.3109/08977199509028968. PMID 8930021.
  6. ↑ "Entrez Gene: MET met proto-oncogene (hepatocyte growth factor receptor)".
  7. 1 2 3 4 5 6 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.
  8. 1 2 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.
  9. ↑ 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.
  10. ↑ 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.
  11. 1 2 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.
  12. ↑ 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.
  13. 1 2 3 4 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.
  14. ↑ Johnson M, Kochhar K, Nakamura T, Iyer A (Jul 1995). "Hepatocyte growth factor-induced signal transduction in two normal mouse epithelial cell lines". Biochemistry and Molecular Biology International 36 (3): 465–74. PMID 7549943.
  15. 1 2 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. 62 (7): 2064–71. PMID 11929826.
  25. ↑ 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.
  26. ↑ Johnson M, Koukoulis G, Matsumoto K, Nakamura T, Iyer A (Jun 1993). "Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells". Hepatology 17 (6): 1052–61. doi:10.1016/0270-9139(93)90122-4. PMID 8514254.
  27. 1 2 "he fields of HGF/c-Met involvement". HealthValue. Retrieved 2009-06-13.
  28. 1 2 3 4 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ Rappolee DA, Iyer A, Patel Y (Jun 1996). "Hepatocyte growth factor and its receptor are expressed in cardiac myocytes during early cardiogenesis". Circulation Research 78 (6): 1028–36. doi:10.1161/01.RES.78.6.1028. PMID 8635233.
  32. ↑ Song W, Majka SM, McGuire PG (1999). "Hepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression". Developmental Dynamics 214 (1): 92–100. doi:10.1002/(SICI)1097-0177(199901)214:1<92::AID-DVDY9>3.0.CO;2-X. PMID 9915579.
  33. 1 2 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 (Dec 2013). "Met signaling in cardiomyocytes is required for normal cardiac function in adult mice". Biochimica et Biophysica Acta 1832 (12): 2204–15. doi:10.1016/j.bbadis.2013.08.008. PMID 23994610.
  34. ↑ Leo C, Sala V, Morello M, Chiribiri A, Riess I, Mancardi D, Schiaffino S, Ponzetto C, Crepaldi T (2011-02-09). "Activated Met signalling in the developing mouse heart leads to cardiac disease". PLOS ONE 6 (2): e14675. doi:10.1371/journal.pone.0014675. PMC 3036588. PMID 21347410.
  35. 1 2 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ "HGF/c-Met and cancer". HealthValue. Retrieved 2009-06-13.
  39. ↑ Kim S, Lee UJ, Kim MN, Lee EJ, Kim JY, Lee MY, Choung S, Kim YJ, Choi YC (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.
  40. ↑ del Carmen MG, Birrer M, Schorge JO (September 2012). "Clear cell carcinoma of the ovary: a review of the literature". Gynecol. Oncol. 126 (3): 481–90. doi:10.1016/j.ygyno.2012.04.021. PMID 22525820.
  41. ↑ 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 (June 2013). "Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer". Cancer Discov 3 (6): 658–73. doi:10.1158/2159-8290.CD-12-0558. PMC 4078408. PMID 23729478.
  42. ↑ Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P (2006). "A genetic variant that disrupts MET transcription is associated with autism". Proc. Natl. Acad. Sci. U.S.A. 103 (45): 16834–9. doi:10.1073/pnas.0605296103. PMC 1838551. PMID 17053076.
  43. ↑ Campbell DB, Buie TM, Winter H, Bauman M, Sutcliffe JS, Perrin JM, Levitt P (2009). "Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions". Pediatrics 123 (3): 1018–24. doi:10.1542/peds.2008-0819. PMID 19255034.
  44. ↑ 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 (2014). "A familial heterozygous null mutation of MET in autism spectrum disorder". Autism Res 7 (5): 617–22. doi:10.1002/aur.1396. PMID 24909855.
  45. ↑ Qiu S, Lu Z, Levitt P (2014). "MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus". J. Neurosci. 34 (49): 16166–79. doi:10.1523/JNEUROSCI.2580-14.2014. PMID 25471559.
  46. ↑ Eagleson KL, Milner TA, Xie Z, Levitt P (2013). "Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus". J. Comp. Neurol. 521 (14): 3241–59. doi:10.1002/cne.23343. PMC 3942873. PMID 23787772.
  47. ↑ Judson MC, Eagleson KL, Levitt P (2011). "A new synaptic player leading to autism risk: Met receptor tyrosine kinase". J Neurodev Disord 3 (3): 282–92. doi:10.1007/s11689-011-9081-8. PMC 3261279. PMID 21509596.
  48. ↑ Qiu S, Anderson CT, Levitt P, Shepherd GM (2011). "Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase". J. Neurosci. 31 (15): 5855–64. doi:10.1523/JNEUROSCI.6569-10.2011. PMC 3086026. PMID 21490227.
  49. ↑ Judson MC, Eagleson KL, Wang L, Levitt P (2010). "Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain". J. Comp. Neurol. 518 (21): 4463–78. doi:10.1002/cne.22467. PMC 2952412. PMID 20853516.
  50. ↑ pmid22958829
  51. ↑ Doherty, Kimberly R.; Wappel, Robert L.; Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Kramer, James W.; Brown, Arthur M.; Shell, Scott A.; Bacus, Sarah (2013-10-01). "Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes". Toxicology and Applied Pharmacology 272 (1): 245–255. doi:10.1016/j.taap.2013.04.027. ISSN 1096-0333. PMID 23707608.
  52. ↑ Aguirre, Shirley A.; Heyen, Jonathan R.; Collette, Walter; Bobrowski, Walter; Blasi, Eileen R. (2010-04-01). "Cardiovascular Effects in Rats following Exposure to a Receptor Tyrosine Kinase Inhibitor". Toxicologic Pathology 38 (3): 416–428. doi:10.1177/0192623310364027. ISSN 0192-6233. PMID 20231546.
  53. ↑ Gallo, Simona; Sala, Valentina; Gatti, Stefano; Crepaldi, Tiziana (2014-10-21). "HGF/Met Axis in Heart Function and Cardioprotection". Biomedicines 2 (4): 247–262. doi:10.3390/biomedicines2040247.
  54. ↑ Sala, V.; Crepaldi, T. (2011-05-01). "Novel therapy for myocardial infarction: can HGF/Met be beneficial?". Cellular and molecular life sciences: CMLS 68 (10): 1703–1717. doi:10.1007/s00018-011-0633-6. ISSN 1420-9071. PMID 21327916.
  55. ↑ 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.
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  78. ↑ Liang Q, Mohan RR, Chen L, Wilson SE (1998). "Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways". Invest. Ophthalmol. Vis. Sci. 39 (8): 1329–38. PMID 9660480.
  79. ↑ Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS 65: 131–65. PMID 8380735.
  80. ↑ Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK (1991). "Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor". EMBO J. 10 (10): 2867–78. PMC 452997. PMID 1655405.
  81. ↑ Hiscox S, Jiang WG (1999). "Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells". Biochem. Biophys. Res. Commun. 261 (2): 406–11. doi:10.1006/bbrc.1999.1002. PMID 10425198.
  82. ↑ Wang D, Li Z, Messing EM, Wu G (2002). "Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM". J. Biol. Chem. 277 (39): 36216–22. doi:10.1074/jbc.M205111200. 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, Ma PC, Morrison PT, Salgia R (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 (2003). "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 (2004). "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. 

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