The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cullis, J; Meiri, D; Sandi, MJ; Radulovich, N; Kent, OA; Medrano, M; Mokady, D; Normand, J; Larose, J; Marcotte, R; Marshall, CB; Ikura, M; Ketela, T; Moffat, J; Neel, BG; Gingras, AC; Tsao, MS; Rottapel, R Cancer Cell
28
181-98
2016
Show Abstract
Cellular transformation by oncogenic RAS engages the MAPK pathway under strict regulation by the scaffold protein KSR-1. Here, we report that the guanine nucleotide exchange factor GEF-H1 plays a critical role in a positive feedback loop for the RAS/MAPK pathway independent of its RhoGEF activity. GEF-H1 acts as an adaptor protein linking the PP2A B' subunits to KSR-1, thereby mediating the dephosphorylation of KSR-1 S392 and activation of MAPK signaling. GEF-H1 is important for the growth and survival of HRAS(V12)-transformed cells and pancreatic tumor xenografts. GEF-H1 expression is induced by oncogenic RAS and is correlated with pancreatic neoplastic progression. Our results, therefore, identify GEF-H1 as an amplifier of MAPK signaling and provide mechanistic insight into the progression of RAS mutant tumors. | 24525234
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