The RhoGEF GEF-H1 Is Required for Oncogenic RAS Signaling via KSR-1

• The GEF-H1 gene is a transcriptional target of the RAS/MAPK pathway
• GEF-H1 potentiates MAPK signaling in HRASV12-transformed cells
• GEF-H1 is a bridging protein that links KSR-1 to the B’ regulatory subunit of PP2A
• GEF-H1 contributes to mutant RAS PDAC xenograft growth

SummaryCellular 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 HRASV12-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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