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Originally published In Press as doi:10.1074/jbc.M105628200 on July 24, 2001

J. Biol. Chem., Vol. 276, Issue 39, 36281-36288, September 28, 2001
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Sphingosine 1-Phosphate and Isoform-specific Activation of Phosphoinositide 3-Kinase beta
EVIDENCE FOR DIVERGENCE AND CONVERGENCE OF RECEPTOR-REGULATED ENDOTHELIAL NITRIC-OXIDE SYNTHASE SIGNALING PATHWAYS*

Junsuke IgarashiDagger and Thomas MichelDagger §

From the Dagger  Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and § Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132

Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that elicits diverse biological responses, including angiogenesis, via the activation of G protein-coupled EDG receptors. S1P activates the endothelial isoform of nitric-oxide synthase (eNOS), associated with eNOS phosphorylation at Ser-1179, a site phosphorylated by protein kinase Akt. We explored the proximal signaling pathways that mediate Akt activation and eNOS regulation by S1P/EDG receptors. Akt is regulated by the lipid kinase phosphoinositide 3-kinase (PI3-K). We found that bovine aortic endothelial cells (BAEC) express both alpha  and beta  isoforms of PI3-K, while lacking the gamma  isoform. S1P treatment led to the rapid and isoform-specific activation of PI3-Kbeta in BAEC. PI3-Kbeta can be regulated by G protein beta gamma subunits (Gbeta gamma ). The overexpression of a peptide inhibitor of Gbeta gamma attenuated S1P-induced eNOS enzyme activation, as well as S1P-induced phosphorylation of eNOS and Akt. In contrast, bradykinin, a classical eNOS agonist, neither activated any PI3-K isoform nor induced eNOS phosphorylation at Ser-1179, despite activating eNOS in BAEC. Vascular endothelial growth factor activated both PI3-Kalpha and PI3-Kbeta via tyrosine kinase pathways and promoted eNOS phosphorylation that was unaffected by Gbeta gamma inhibition. These findings indicate that PI3-Kbeta (regulated by Gbeta gamma ) may represent a novel molecular locus for eNOS activation by EDG receptors in vascular endothelial cells. These studies also indicate that different eNOS agonists activate distinct signaling pathways that diverge proximally following receptor activation but converge distally to activate eNOS.

* This work was supported by the National Institutes of Health (to T. M.) and the Burroughs Wellcome Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work is dedicated to the memory of Professor Eva J. Neer, whose seminal work on the signaling roles of G protein beta gamma subunits established a new paradigm in signal transduction and whose scientific insights continue to inspire.

To whom correspondence should be addressed: Cardiovascular Division, Brigham and Women's Hospital, Thorn Bldg., Rm. 1210A, 75 Francis St., Boston, MA 02115. Tel.: 617-732-7376; Fax: 617-732-5132; E-mail: michel@calvin.bwh.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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