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.

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The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and whole-kinome proteomics to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. We have identified essential kinases that manage biosynthetic stress indicative of the ovarian cancer transformed state. These data suggest that targeting pathways that underlie adaptation to cellular stress states rather than driver oncogenes may provide new therapeutic avenues for treating HGSC. Citation Format: Kyle Francis, Helen Burston, Daphna Mokady, Melany Wagner, Mauricio Medrano, Robert Rottapel. Functional genetic architecture of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA27.

Cellular transformation by oncogenic RAS engages the MAPK pathway under strict spatiotemporal regulation by the scaffold protein KSR-1. Here, we find using a whole genome functional shRNA-based screen, that the guanine nucleotide exchange factor GEF-H1 plays a critical role in a positive feedback loop for the RAS/MAPK pathway independently of its RhoGEF activity. GEF-H1 acts as an adaptor protein, linking the PP2A B' subunits to KSR-1, required for the dephosphorylation of KSR-1 S392 and activation of MAPK signaling. GEF-H1 is required for the growth and survival of RASV12-transformed cells and pancreatic 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 required for cell transformation and provide mechanistic insight into the progression of RAS-mutant tumors. Citation Format: Jane Cullis, Dedi Meiri, Maria Jose-Sandi, Oliver Kent, Mauricio Medrano, Daphna Mokady, Ming Tsao, Anne-Claude Gingras, Robert Rottapel. The RhoGEF GEF-H1 is required for RAS oncogene-driven pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B31. doi: 10.1158/1557-3125.RASONC14-B31