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. 2006 Jan 27;281(4):1921-8.
doi: 10.1074/jbc.M506035200. Epub 2005 Nov 21.

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

Linnia H Mayeenuddin  1 , James C Garrison
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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

Linnia H Mayeenuddin et al. J Biol Chem. .
Free article

Abstract

Rac activation is a key step in chemotaxis of hematopoietic cells, which is both positively and negatively regulated by receptors coupled to heterotrimeric G proteins. P-Rex1, a Rac-specific guanine nucleotide exchange factor, is dually activated by phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)) and the Gbetagamma subunits of heterotrimeric G proteins. This study explored the regulation of P-Rex1 by phosphorylation with the cAMP-dependent protein kinase (protein kinase A) in vitro and by G(i)- and G(s)-coupled receptors in HEK293T cells. P-Rex1 isolated from Sf9 and HEK293T cells migrates as two distinct bands that are partially phosphorylated. Phosphorylation of P-Rex1 with protein kinase A (PKA) inhibits the PIP(3)- and Gbetagamma-stimulated P-Rex1 guanine nucleotide exchange activity on Rac. The guanine nucleotide exchange factor activity of three different forms of P-Rex1 (native Sf9, de-phosphorylated, and phosphorylated) was examined in the presence of PIP(3) and varying concentrations of Gbeta(1)gamma(2). Gbeta(1)gamma(2) was 47-fold less potent in activating the phosphorylated form of P-Rex1 compared with the de-phosphorylated form. HEK293T cells expressing P-Rex1 were labeled with (32)P and stimulated with lysophosphatidic acid (LPA) to release Gbetagamma or isoproterenol to activate PKA. Treatment with isoproterenol or S(p)-cAMPS, a potent activator of PKA, increased the incorporation of (32)P into P-Rex1. LPA increased the amount of GTP-bound Rac in the cells and isoproterenol reduced basal levels of GTP-bound Rac and blunted the effect of LPA. Treatment of the cells with S(p)-cAMPS also reduced the levels of GTP-bound Rac. These results outline a novel mechanism for G(s)-linked receptors to regulate the function of P-Rex1 and inhibit its function in cells.

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