Abstract：
: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 phosphatidylinositol 3-kinase (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 demonstrated previously that mammalian target of rapamycin, an important effector and regulator of PI3K/AKT, activates phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), a Rac guanine nucleotide exchange factor identified as a target of G betagamma 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, because 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, and signaling to extracellular signal-regulated kinase in response to either angiogenic factor is not sensitive to P-Rex1 knockdown. We also demonstrate that in endothelial cells, VEGF promotes an increase in the expression of endogenous P-Rex1 and 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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Carretero-Ortega J,Walsh CT,Hernández-García R,Reyes-Cruz G,Brown JH,Vázquez-Prado Jdoi
10.1124/mol.109.060400subject
Has Abstractpub_date
2010-03-01 00:00:00pages
435-42issue
3eissn
0026-895Xissn
1521-0111pii
mol.109.060400journal_volume
77pub_type
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
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更新日期：1994-09-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1997-03-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1993-08-01 00:00:00
abstract：:Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; (S)-HPMPC] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir also possesses potent activity against human papillomavirus-induced tumors in animal models and patients. We have recent...
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journal_title：Molecular pharmacology
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更新日期：1990-03-01 00:00:00
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