Disease relevance of PREX1

• When transfected in pheochromocytoma PC12 cells, P-Rex1 can be activated by NGF, causing an increase in GTP-bound Rac1 and cell motility [1].

High impact information on PREX1

• P-Rex1 appears to be a coincidence detector in PtdIns(3,4,5)P3 and Gbetagamma signaling pathways that is particularly adapted to function downstream of heterotrimeric G proteins in neutrophils [2].
• P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac [2].
• Phosphorylation of P-Rex1 by the cyclic AMP-dependent protein kinase inhibits the phosphatidylinositiol (3,4,5)-trisphosphate and Gbetagamma-mediated regulation of its activity [3].
• Treatment with isoproterenol or S(p)-cAMPS, a potent activator of PKA, increased the incorporation of (32)P into P-Rex1 [3].
• Deletion of the DEP, PDZ, or inositol polyphosphate 4-phosphatase homology domains has no major consequences on the abilities of either PtdIns(3,4,5)P3 or Gbetagamma subunits to stimulate P-Rex1 Rac-GEF activity [4].

Biological context of PREX1

• We have investigated here the mechanisms of stimulation of P-Rex1 Rac-GEF activity by the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) and the Gbetagamma subunits of heterotrimeric G proteins [4].
• Redistribution of P-Rex1 to the leading edge was also dependent on tyrosine kinase activity and was modulated by cell adhesion [5].
• As a selective catalyst for Rac2 activation, P-Rex1 serves as an important regulator of human neutrophil NADPH oxidase activity and chemotaxis in response to a variety of extracellular stimuli [5].
• P-Rex2 has structure, activity and regulatory properties similar to P-Rex1 but has divergent tissue distribution, as P-Rex1 is mainly expressed in neutrophils [6].
• PREX is a positive regulatory element for xenobiotic responsive element (XRE)-mediated gene expression that is located upstream of the XRE in the CYP2A8 gene [7].

Anatomical context of PREX1

• PI 3,4,5-trisphosphate [PI(3,4,5)P(3); PIP(3)]-dependent Rac exchanger 1 (P-Rex1) is a Rac-specific guanine nucleotide exchange factor abundant in neutrophils and myeloid cells [5].
• The exchange activity of P-Rex1 is synergistically activated by the binding of PIP(3)and betagamma subunits of heterotrimeric G proteins in vitro, suggesting that the association of P-Rex1 with membranes is a prerequisite for cellular activation [5].

Associations of PREX1 with chemical compounds

• HEK293T cells expressing P-Rex1 were labeled with (32)P and stimulated with lysophosphatidic acid (LPA) to release Gbetagamma or isoproterenol to activate PKA [3].

Other interactions of PREX1

• However, the spatial regulation of endogenous P-Rex1 has not been well defined, particularly in human neutrophils activated through G protein-coupled receptors [5].
• P-Rex1 is mainly expressed in neutrophils and regulates reactive oxygen species formation in these cells (Welch et al., 2002), whereas P-Rex2 is expressed in a wide variety of tissues but not in neutrophils (Donald et al., 2004), and P-Rex2B is expressed in the heart (Rosenfeldt et al., 2004) [8].

Analytical, diagnostic and therapeutic context of PREX1

• In situ hybridization revealed that P-Rex1 is dynamically expressed in a variety of cells in the developing mouse brain, including some cortical and DRG neurons [1].

References