P-Rex1 ( BC067047; G630042G04; KIAA1415; mKIAA1415; Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger; PREX1; P-Rex1), P-Rex2 ( DEP domain containing 2; DEP.2; Depdc2; phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 2; PREX2; P-Rex2; PtdIns(3,4,5)-dependent Rac exchanger 2)
A phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger (P-Rex) is an intracellular signaling molecule that regulates leukocyte function and neuronal development by activating a small guanine nucleotide-binding protein, Rac. The Homo sapiens genome encodes two P-Rex genes, P-Rex1 and P-Rex2. In 2002, Welch et al. purified a PIP3-dependent Rac activator from pig neutrophil lysates, identified a 196 kDa Dbl-like GEF (guanine nucleotide exchange factor) protein for Rac, and designated it as P-Rex1 (Welch et al. 2002). They characterized its synergistic activation by Gβγ subunits of heterotrimeric G proteins and PIP3, and its physiological function in reactive oxygen species (ROS) production in neutrophils (Welch et al. 2002). P-Rex2 and the spliced variant, P-Rex2B, were identified in a search for P-Rex1-homologous genes (Donald et al. 2004; Rosenfeldt et al. 2004). Using P-Rex knockout mice, Welch et al. and the other group clarified physiological roles of P-Rex genes in peripheral white blood cells and in neuronal development (Donald et al. 2008; Dong et al. 2005; Welch et al. 2005). Recently, several studies indicated the involvement of P-Rex genes in proliferation and metastasis of human tumors. Especially, Fine et al. demonstrated that P-Rex2 activates the PI3K ( phosphoinositide 3-kinase) pathway by a direct inhibition of PTEN (phosphatase and tensin homolog) (Fine et al. 2009). For more detailed information, the review of P-Rex is available (Welch 2015).
Molecular Structure and Regulation
P-Rex plays important roles in Rac-mediated actin polymerization that leads to lamellipodia formation, ROS production, and transcriptional regulation. P-Rex1 is highly expressed in peripheral blood leukocytes and the brain (Donald et al. 2008; Welch et al. 2002; Yoshizawa et al. 2005), and P-Rex2 is abundant in the lung and brain (Donald et al. 2008). In contrast to P-Rex1, expressed widely throughout the whole brain (Donald et al. 2008; Yoshizawa et al. 2005), P-Rex2 expression is more restricted to the cerebellum (Donald et al. 2008). P-Rex2B expression was shown, by northern blots, to be only in the heart (Donald et al. 2004). Knockout mice of P-Rex1 (Donald et al. 2008; Dong et al. 2005; Hill et al. 2005) and P-Rex2 (Donald et al. 2008) revealed their physiological and developmental roles. In peripheral blood leukocytes, P-Rex1 is involved in GPCR (G protein-coupled receptor)-dependent Rac activation, ROS production, cell migration, and cell adhesion (Dong et al. 2005; Lawson et al. 2011; Welch et al. 2002, 2005). P-Rex1 knockout mice also exhibit defects of Rac1 activation, cell migration, and superoxide production in macrophages (Wang et al. 2008). P-Rex2 regulates dendrite structure in mouse cerebellar Purkinje cells (Donald et al. 2008). P-Rex1/P-Rex2 double knockout mice grow up healthy and are fertile but show morphological defects in cerebellar Purkinje cells and a strong motor coordination defect (Donald et al. 2008).
Roles in Cancer
Overexpression of Rho-family GTPases and GEFs participates in cancer progression and metastasis in various types of tumors. Recently, several studies indicated the involvement of P-Rex genes in proliferation and metastasis in breast and prostate tumors (Fine et al. 2009; Kim et al. 2011; Montero et al. 2011; Qin et al. 2009; Sosa et al. 2010). The human P-Rex1 gene is located on the chromosome 20q13, which is a region frequently amplified in breast cancer, and P-Rex2 gene is on the chromosome 8q13, a region of high amplification in breast, prostate, ovarian, and colorectal cancers. Indeed, it has been recently reported that P-Rex1 mediates Erb2-dependent migration and tumorigenesis in breast cancer cells (Montero et al. 2011; Sosa et al. 2010) and promotes spontaneous metastasis in prostate cancer cells (Qin et al. 2009). P-Rex2 is also highly expressed in several human cancers and directly inhibits phosphatase activity of PTEN (Fine et al. 2009), which is a tumor suppressor frequently mutated in human cancers and an enzyme that dephosphorylates PI(3,4,5)P3 into PI(4,5)P2. P-Rex2-mediated inhibition of PTEN accumulates PIP3 and consequently promotes cell proliferation with activation of Akt in breast cancer cells (Fine et al. 2009).
Summary and Perspective
P-Rex proteins function as Rac activators and are involved in ROS production, cell morphology, migration, proliferation, and gene expression in various cells and tissues. P-Rex is activated by heterotrimeric G proteins, RTK and PI3K-pathways, and inhibited by cAMP/PKA signals, allowing it to potentially integrate various hormonal stimuli into a Rac signaling. It is unclear how P-Rex keeps basal activity low and is activated by Gβγ and the molecules. Although the catalytic core structure of P-Rex1 including DH/PH domains was reported (Cash et al. 2016), whole structure analysis of P-Rex should provide insights into understanding the regulation mechanisms. Higher expression level of P-Rex1 is linked to malignancy in human breast and prostate tumors, and potentiates RTK signals. However, the mechanisms of how RTK signals activate P-Rex/Rac pathway have not been clarified. Two potential mechanisms for activation of P-Rex pathways indirectly through transactivation of G proteins or by phosphorylation and dephosphorylation control of P-Rex by RTK signaling have been described, but a more detailed analysis should yield better understanding of multiple P-Rex1 regulations.