The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

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Jane Cullis, David Meiri, Maria Jose Sandi, Nikolina Radulovich, Oliver A Kent, Mauricio Medrano, Daphna Mokady, Josee Normand, Jose Larose, Richard Marcotte, Christopher B Marshall, Mitsuhiko Ikura, Troy Ketela, Jason Moffat, Benjamin G Neel, Anne-Claude Gingras, Ming-Sound Tsao, Robert Rottapel. The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer cell. 2014 Feb 10;25(2):181-95

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PMID: 24525234

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