Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Y. Lissanu Deribe, Y. Shi, K. Rai, L. Nezi, S.B. Amin, C.C. Wu, K.C. Akdemir, M. Mahdavi, Q. Peng, Q.E. Chang, K. Hornigold, S.T. Arold, H.C. Welch, L.A. Garraway, L. Chin
Proc Natl Acad Sci USA, 113(9), E1296-E1305, (2016)

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Keywords

PREX2, melanoma, Rac1, PI3K/Akt, mouse models of cancer

Abstract

​Mutations in the PI3K/PTEN/Akt signaling pathway occur frequently across multiple tumor types. These mutations primarily serve to activate PI-3 and Akt kinases. PREX2 is a guanine nucleotide exchanger for Rac1 that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Here we report that a mouse model of a truncating PREX2 mutation shows accelerated melanoma development in the context of mutant NRAS. Truncating PREX2 mutations have increased Rac1 guanine nucleotide exchange factor activity, and tumors harboring these mutations have elevated PI3K/Akt pathway activation and reduced expression of critical negative cell cycle regulators leading to increased cell proliferation. This work provides evidence for a previously unidentified mechanism of activating Rac1, the PI3K pathway, and regulation of cell cycle progression in melanoma.

Code

DOI: 10.1073/pnas.1513801113

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