MET in type 1 papillary renal cell carcinoma (WP4205)
MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of Tyr1234 and Tyr1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program; proliferation and survival (resistance to apoptotic signals), increased cell motility, cell dissociation (scattering), epithelial tubulogenesis, infiltration of tissues, and stimulation of angiogenesis (Appleman et al). The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of PI3K, or indirectly through the scaffolding protein GAB1. Phosphorylation of Tyr1349 and Tyr1356 of the multisubstrate docking site mediates 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. GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signaling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways. (Description adapted from [https://en.wikipedia.org/wiki/C-Met Wikipedia]). MET is a proto-oncogene, meaning that regulated expression of the wild-type allele plays a role in normal physiologic processes, and malignant transformation occurs when MET activity is increased in- appropriately and/or constitutively activated (Appleman et al).
Authors
Kristina Hanspers , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , Finterly Hu , and Eric WeitzCited In
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Organism
Homo sapiensCommunities
CPTAC Diseases Renal Genomics PathwaysAnnotations
Disease Ontology: papillary renal cell carcinoma cancer
Cell Type Ontology: endothelial cell epithelial cell
Participants
References
- Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000 Nov 20;19(49):5582–9. PubMed Europe PMC Scholia
- Giubellino A, Linehan WM, Bottaro DP. Targeting the Met signaling pathway in renal cancer. Expert Rev Anticancer Ther. 2009 Jun;9(6):785–93. PubMed Europe PMC Scholia
- Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 2010 May;46(7):1260–70. PubMed Europe PMC Scholia
- Appleman LJ. MET signaling pathway: a rational target for cancer therapy. J Clin Oncol. 2011 Dec 20;29(36):4837–8. PubMed Europe PMC Scholia
- Organ SL, Tsao M-S. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011 Nov;3(1 Suppl):S7–19. PubMed Europe PMC Scholia
- Fay AP, Signoretti S, Choueiri TK. MET as a target in papillary renal cell carcinoma. Clin Cancer Res. 2014 Jul 1;20(13):3361–3. PubMed Europe PMC Scholia
- Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med. 2016 Jan 14;374(2):135–45. PubMed Europe PMC Scholia