Regulation and function of P-Rex family Rac-GEFs

Abstract

The P-Rex family are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins.They are distinguished from other Rac-GEFs through their synergistic mode of activation by the lipid second messenger phosphatidyl inositol (3,4,5) trisphosphate and the Gbg subunits of heterotrimeric G proteins, thus acting as coincidence detectors for phosphoinositide 3-kinase and G protein coupled receptor signaling.Work in geneticallymodified mice has shown that P-Rex1 has physiological importance in the inflammatory response and the migration of melanoblasts during development, whereas P-Rex2 controls the dendrite morphology of cerebellar Purkinj.neurons as well as glucose homeostasis in liver and adipose tissue.Deregulation of P-Rex1 and P-Rex2 expression occurs in many types of cancer, and P-Rex2 is frequently mutated in melanoma.Both GEFs promote tumor growth or metastasis.This review critically evaluates the P-Rex literature and tools available and highlights exciting recent developments and open questions.