Methionine adenosyltransferase 2B-GIT1 complex serves as a scaffold to regulate Ras/Raf/MEK1/2 activity in human liver and colon cancer cells.

The American Journal of Pathology
Hui PengShelly C Lu

Abstract

Methionine adenosyltransferase 2B (MAT2B) encodes for variant proteins V1 and V2 that interact with GIT1 to increase ERK activity and growth in human liver and colon cancer cells. MAT2B or GIT1 overexpression activates MEK. This study explores the mechanism for MEK activation. We examined protein-protein interactions by co-immunoprecipitation and verified by confocal microscopy and pull-down assay using recombinant or in vitro translated proteins. Results were confirmed in an orthotopic liver cancer model. We found that MAT2B and GIT1-mediated MEK1/2 activation was not mediated by PAK1 or Src in HepG2 or RKO cells. Instead, MAT2B and GIT1 interact with B-Raf and c-Raf and enhance recruitment of Raf proteins to MEK1/2. MAT2B-GIT1 activates c-Raf, which is the key mediator for MEK/12 activation, because this still occurred in RKO cells that express constitutively active B-Raf mutant. The mechanism lies with the ability of MAT2B-GIT1 to activate Ras and promote B-Raf/c-Raf heterodimerization. Interestingly, MAT2B but not GIT1 can directly interact with Ras, which increases protein stability. Finally, increased Ras-Raf-MEK signaling occurred in phenotypically more aggressive liver cancers overexpressing MAT2B variants and GIT1. In ...Continue Reading

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Citations

Aug 23, 2016·PloS One·Claudia PérezMaría A Pajares
Dec 1, 2017·Antioxidants & Redox Signaling·María A Pajares, Dolores Pérez-Sala
Sep 12, 2018·Expert Review of Proteomics·José M MatoFernando J Corrales
Jul 12, 2019·Animal Science Journal = Nihon Chikusan Gakkaihō·Cunzhen ZhaoKaiwei Deng
Feb 25, 2020·The Biochemical Journal·Maicol ManciniEric Fabbrizio
Sep 17, 2017·Oncotarget·Lian LiuPei-Yuan Li
Sep 10, 2019·World Journal of Gastroenterology : WJG·Ben MurrayShelly C Lu
Nov 17, 2017·Experimental Biology and Medicine·Lauren Y MaldonadoShelly C Lu
Sep 26, 2017·Journal of Proteome Research·María Isabel MoraFernando José Corrales

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