TY - JOUR T1 - P-Rex1, a guanine nucleotide exchange factor for Rac, mediates angiogenic responses to SDF-1/CXCL-12 linked to Rac activation, endothelial cell migration and in vitro angiogenesis JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.060400 SP - mol.109.060400 AU - Jorge Carretero-Ortega AU - Colin T. Walsh AU - Ricardo Hernandez-Garcia AU - Guadalupe Reyes-Cruz AU - Joan Heller Brown AU - Jose Vazquez-Prado Y1 - 2009/12/17 UR - http://molpharm.aspetjournals.org/content/early/2009/12/17/mol.109.060400.abstract N2 - Stromal cell-derived Factor-1 (SDF-1/CXCL-12) and Vascular Endothelial Growth Factor (VEGF), which can be secreted by hypoxic tumors, promote the generation of new blood vessels. These potent angiogenic factors stimulate endothelial cell migration via the activation of Rho GTPases and the PI3K/AKT signaling pathway. Thus characterization of guanine nucleotide exchange factors critical in the angiogenic signaling cascades offers the possibility of identifying novel molecular targets. We previously demonstrated that mTOR, an important effector and regulator of PI3K/AKT, activates P-Rex1, a Rac guanine nucleotide exchange factor identified as a target of Gβγ and PI3K, via direct interactions. In this study we tested the hypothesis that P-Rex1 is involved in the angiogenic responses elicited by SDF-1 and VEGF. Using a knockdown approach, we demonstrate that P-Rex1 is indeed required for SDF-1 promoted signaling pathway, as there is decreased Rac activation, cell migration and in vitro angiogenesis in P-Rex1 knockdown cells stimulated with SDF-1. In contrast P-Rex1 knockdown does not affect responses to VEGF nor is signaling to ERK in response to either angiogenic factor sensitive to P-Rex1 knockdown. We also demonstrate that in endothelial cells, VEGF promotes an increase in the expression of endogenous P-Rex1 as well as the SDF-1 receptor CXCR4; in addition, VEGF-pretreated cells show an increased migratory and angiogenic response to SDF-1, suggesting that VEGF stimulation can complement SDF-1/CXCR4 signaling to induce angiogenesis. We conclude that P-Rex1 is a key element in SDF-1-induced angiogenic responses and a potential target for therapeutic intervention.The American Society for Pharmacology and Experimental Therapeutics ER -