Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

P-Rex

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_182

Synonyms

Historical Background

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

In vitro, P-Rex catalyzes guanine nucleotide exchange on Rac and Cdc42, but not Rho (Welch et al. 2002). However, P-Rex specifically activates Rac in vivo (Welch et al. 2002). P-Rex activity is positively and negatively regulated by heterotrimeric G protein signals (Mayeenuddin and Garrison 2006; Welch et al. 2002). P-Rex is directly and synergistically activated by Gβγ and PIP3, which is produced by PI3K in vivo, and is inhibited by direct phosphorylation by cAMP-dependent kinase (Protein kinase A; PKA) (Mayeenuddin and Garrison 2006; Urano et al. 2008). The human P-Rex1 and P-Rex2 are highly related 1659 and 1606 amino acid proteins containing an amino-terminal DH (Dbl-homology), a PH (Pleckstrin homology), two DEP (Dishevelled, Egl-10, and Pleckstrin), two PDZ (PSD-95, Dlg, and ZO-1), and a carboxyl-terminal IP4P (inositol polyphosphate 4-phosphatase)- like domains (Fig. 1). The tandem DH/PH domains are minimal and constitutively active elements that catalyze the exchange of guanine nucleotide on Rac. The DH domain possesses the catalytic core and is thought to be directly stimulated by Gβγ (Hill et al. 2005). The PH domain mediates PIP 3-dependent activation (Hill et al. 2005), promotes translocation of P-Rex from cytosol to plasma membrane (Barber et al. 2007), and confers its substrate specificity (Joseph and Norris 2005). Functions of tandem DEP and PDZ domains have been unclear, but these domains keep the basal GEF activity low (Hill et al. 2005) and mediate Gβγ-dependent activation through their interaction with IP4P-like domain (Urano et al. 2008). The IP4P-like domain shows a significant similarity to inositol polyphosphate 4-phosphatase (Donald et al. 2004; Rosenfeldt et al. 2004; Welch et al. 2002), but its phosphatase activity has not been characterized. Truncation mutants of P-Rex1 indicated that the DH/PH domains act as a constitutively active form, and the other domains contribute to keep low basal activity (Hill et al. 2005).
P-Rex, Fig. 1

Domain structure of P-Rex1, P-Rex2, and P-Rex2B

In addition to heterotrimeric G proteins, several receptor tyrosine kinases (RTK) indirectly activate P-Rex1 in a PI3K-dependent manner. The P-Rex activation regulates cell morphology and migration in neuronal cells and human tumor cells (Montero et al. 2011; Qin et al. 2009; Sosa et al. 2010; Yoshizawa et al. 2005) (Fig. 2). In breast cancer cells, heregulins/neuregulins and their receptors, the ErbB subfamily of RTKs, activate P-Rex1 through the transactivation of CXCR (CXC chemokine receptor) and PI3K (Sosa et al. 2010). Neuregulin also regulates P-Rex activity through dephosphorylation of inhibitory residues and phosphorylation of activating residues of P-Rex1 (Montero et al. 2011), although kinases and phosphatases which regulate the phosphorylations have not been clarified yet. Moreover, P-Rex mediates Rac activation and cell migration with  mTOR (mammalian target of rapamycin) (Hernandez-Negrete et al. 2007; Kim et al. 2011), which is a serine-threonine kinase activated by growth factors and nutrient stress. P-Rex1, P-Rex2, and P-Rex2B directly interact with mTOR through the tandem DEP domains (Hernandez-Negrete et al. 2007), but the mechanism of how mTOR modulates P-Rex activity remains unclear.
P-Rex, Fig. 2

Signaling pathways mediated through P-Rex1 and P-Rex2. Direct regulation was indicated as solid lines. Indirect activation was shown as dashed line

Physiological Roles

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.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.TEMASEK Life Science LaboratoryNational University of SingaporeSingaporeSingapore
  2. 2.Division of Biomedical ScienceNara Institute of Science and TechnologyIkoma, NaraJapan