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

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

doi:10.1016/j.ccr.2014.01.025

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

Cancer Cell. 2014 Feb 10;25(2):181-95. doi: 10.1016/j.ccr.2014.01.025.

Authors

Jane Cullis¹, David Meiri², Maria Jose Sandi², Nikolina Radulovich³, Oliver A Kent², Mauricio Medrano¹, Daphna Mokady², Josee Normand², Jose Larose², Richard Marcotte², Christopher B Marshall², Mitsuhiko Ikura¹, Troy Ketela⁴, Jason Moffat⁴, Benjamin G Neel⁵, Anne-Claude Gingras⁶, Ming-Sound Tsao¹, Robert Rottapel⁷

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
² Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada.
³ Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁴ Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Donnelly Centre and Banting and Best Department of Medical Research, 160 College Street, Room 8-804, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵ Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁶ Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 992A, Toronto, ON M5G 1X5, Canada.
⁷ Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Rheumatology, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Electronic address: rottapel@uhnresearch.ca.

PMID: 24525234
DOI: 10.1016/j.ccr.2014.01.025

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Animals
Cell Transformation, Neoplastic / pathology*
Cells, Cultured
Embryo, Mammalian / cytology
Embryo, Mammalian / metabolism
Fibroblasts / cytology
Fibroblasts / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Immunoenzyme Techniques
Mice
NIH 3T3 Cells
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Phosphorylation
Promoter Regions, Genetic / genetics
Protein Kinases / genetics
Protein Kinases / metabolism*
Rho Guanine Nucleotide Exchange Factors / genetics
Rho Guanine Nucleotide Exchange Factors / metabolism*
Signal Transduction
Tumor Cells, Cultured
ras Proteins / genetics
ras Proteins / metabolism*

Substances

ARHGEF2 protein, human
Arhgef2 protein, mouse
Rho Guanine Nucleotide Exchange Factors
Protein Kinases
KSR-1 protein kinase
ras Proteins

Grants and funding

Canadian Institutes of Health Research/Canada