Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 22, Pages 19672-19677Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M009993200
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Funding
- NHLBI NIH HHS [R01 HL57665, HL64793, HL61371] Funding Source: Medline
- NIDDK NIH HHS [DK45659] Funding Source: Medline
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Sphingosine l-phosphate (SPP) binds to members of the endothelial differentiation gene family (EDG) of receptors and leads to diverse signaling events including cell survival, growth, migration and differentiation. However, the mechanisms of how SPP activates these proangiogenic pathways are poorly understood. Here we show that SPP signals through the EDG-1 receptor to the heterotrimeric G protein Gi, leading to activation of the serine/threonine kinase Akt and phosphorylation of the Akt substrate, endothelial nitric-oxide synthase (eNOS). Inhibition of Gi signaling, and phosphoinositide 3-kinase (PI3-kinase) activity resulted in a decrease in SPP-induced endothelial cell chemotaxis. SPP also stimulates eNOS phosphorylation and NO release and these effects are also attenuated by inhibition of Gi signaling, PI 3-kinase, and Akt. However, inhibition of NO production did not influence SPP-induced chemotaxis but effectively blocked the chemotactic actions of vascular endothelial growth factor. Thus, SPP signals through Gi and PI 3-kinase leading to Akt activation and eNOS phosphorylation.
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