title: The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1.
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.
authors: 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.
authors: Jane
authors: J
authors: Cullis
authors: 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.
authors: David
authors: D
authors: Meiri
authors: 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.
authors: Maria Jose
authors: MJ
authors: Sandi
authors: 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.
authors: Nikolina
authors: N
authors: Radulovich
authors: 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.
authors: Oliver A
authors: OA
authors: Kent
authors: 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.
authors: Mauricio
authors: M
authors: Medrano
authors: 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.
authors: Daphna
authors: D
authors: Mokady
authors: 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.
authors: Josee
authors: J
authors: Normand
authors: 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.
authors: Jose
authors: J
authors: Larose
authors: 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.
authors: Richard
authors: R
authors: Marcotte
authors: 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.
authors: Christopher B
authors: CB
authors: Marshall
authors: 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.
authors: Mitsuhiko
authors: M
authors: Ikura
authors: 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.
authors: Troy
authors: T
authors: Ketela
authors: 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.
authors: Jason
authors: J
authors: Moffat
authors: 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.
authors: Benjamin G
authors: BG
authors: Neel
authors: 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.
authors: Anne-Claude
authors: AC
authors: Gingras
authors: 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.
authors: Ming-Sound
authors: MS
authors: Tsao
authors: 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.
authors: Robert
authors: R
authors: Rottapel
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; C577402:Arhgef2 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D018631:ras Proteins