Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 (PREX2)

Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 (PREX2) is a large, multi-domain guanine nucleotide exchange factor (GEF) specific for Rac-type Rho GTPases, mainly acting on Rac1[1][4][5]. PREX2 is activated by phosphoinositide phosphates (especially PIP3) and Gβγ subunits released from G protein-coupled receptors[1][4]. It functions both as a GEF catalyzing the exchange of GDP for GTP on Rac1—thereby activating Rac1—and as a regulator in signaling complexes. PREX2 physically interacts with the tumor suppressor PTEN and can inhibit PTEN’s lipid phosphatase activity, thus enhancing PI3K/AKT pathway signaling and promoting tumorigenesis and cell proliferation[1][3][4][5]. Mutations or overexpression of PREX2, particularly truncating mutations, are frequent in melanoma and other cancers, where they drive oncogenic signaling by disrupting its regulatory interactions with PTEN and promoting Rac1/PI3K/Akt signaling cascades[2][3][5]. PREX2 is therefore considered a potential therapeutic target, especially in cancers driven by dysregulated PI3K/PTEN/Rac1 pathways.

Other names

P-Rex2DEPDC2PPP1R129DEP domain-containing protein 2Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2PtdIns(3,4,5)P3-dependent Rac exchange factor 2FLJ12987

Inhibitors would likely act by blocking PREX2’s GEF activity on Rac1 or by disrupting its interaction with PTEN or other regulatory proteins[2][3][5].