Negative regulation of MET activity

Stable Identifier
R-HSA-6807004
Type
Pathway
Species
Homo sapiens
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Summation

Signaling by MET receptor is negatively regulated mainly by MET receptor dephosphorylation or MET receptor degradation. Protein tyrosine phosphatase PTPRJ dephosphorylates MET tyrosine residue Y1349, thus removing the docking site for the GAB1 adapter (Palka et al. 2003). Protein tyrosine phosphatases PTPN1 and PTPN2 dephosphorylate MET tyrosines Y1234 and Y1235 in the kinase activation loop, thus attenuating catalytic activity of MET (Sangwan et al. 2008). The E3 ubiquitin ligase CBL promotes ubiquitination of the activated MET receptor and subsequent MET degradation. CBL contains a RING finger domain that engages E2 protein ubiquitin ligases to mediate ubiquitination of MET, which may occur at the cell membrane or in the early endocytic compartment. Ubiquitinated MET is degraded in a late endosomal or lysosomal compartment in a proteasome-dependent manner. The involvement of proteasome in MET degradation seems to be indirect, through an effect on MET endocytic trafficking (Jeffers et al. 1997, Peschard et al. 2001, Hammond et al. 2001, Petrelli et al. 2002). LRIG1 promotes lysosome-dependent degradation of MET in the absence of HGF-mediated activation (Lee et al. 2014, Oh et al. 2014).
MET-mediated activation of RAS signaling is inhibited by MET receptor binding to MUC20 (Higuchi et al. 2004) or RANBP10 (Wang et al. 2004).

Literature References
PubMed ID Title Journal Year
11894096 The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met

Petrelli, A, Gilestro, GF, Lanzardo, S, Comoglio, PM, Migone, N, Giordano, S

Nature 2002
9001234 Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway

Jeffers, M, Taylor, GA, Weidner, KM, Omura, S, Vande Woude, GF

Mol. Cell. Biol. 1997
23208509 Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody

Lee, JM, Kim, B, Lee, SB, Jeong, Y, Oh, YM, Song, YJ, Jung, S, Choi, J, Lee, S, Cheong, KH, Kim, DU, Park, HW, Han, YK, Kim, GW, Choi, H, Song, PH, Kim, KA

Oncogene 2014
14684163 A novel MET-interacting protein shares high sequence similarity with RanBPM, but fails to stimulate MET-induced Ras/Erk signaling

Wang, D, Li, Z, Schoen, SR, Messing, EM, Wu, G

Biochem. Biophys. Res. Commun. 2004
11420688 Down-regulation of MET, the receptor for hepatocyte growth factor

Hammond, DE, Urbé, S, Vande Woude, GF, Clague, MJ

Oncogene 2001
12475979 Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1

Palka, HL, Park, M, Tonks, NK

J. Biol. Chem. 2003
18819921 Regulation of the Met receptor-tyrosine kinase by the protein-tyrosine phosphatase 1B and T-cell phosphatase

Sangwan, V, Paliouras, GN, Abella, JV, Dubé, N, Monast, A, Tremblay, ML, Park, M

J. Biol. Chem. 2008
11741535 Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein

Peschard, P, Fournier, TM, Lamorte, L, Naujokas, MA, Band, H, Langdon, WY, Park, M

Mol. Cell 2001
15314156 MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met

Higuchi, T, Orita, T, Katsuya, K, Yamasaki, Y, Akiyama, K, Li, H, Yamamoto, T, Saito, Y, Nakamura, M

Mol. Cell. Biol. 2004
24828152 USP8 modulates ubiquitination of LRIG1 for Met degradation

Oh, YM, Lee, SB, Choi, J, Suh, HY, Shim, S, Song, YJ, Kim, B, Lee, JM, Oh, SJ, Jeong, Y, Cheong, KH, Song, PH, Kim, KA

Sci Rep 2014
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