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https://hdl.handle.net/2440/56942
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Type: | Journal article |
Title: | Sphingosine kinase-1 associates with Integrin alpha(V)beta(3) to mediate endothelial cell survival |
Author: | Gamble, J. Sun, W. Li, X. Hahn, C. Pitson, S. Vadas, M. Bonder, C. |
Citation: | American Journal of Pathology, 2009; 175(5):2217-2225 |
Publisher: | Amer Soc Investigative Pathology Inc |
Issue Date: | 2009 |
ISSN: | 0002-9440 1525-2191 |
Statement of Responsibility: | Jennifer R. Gamble, Wai Y. Sun, Xiaochun Li, Christopher N. Hahn, Stuart M. Pitson, Mathew A. Vadas and Claudine S. Bonder |
Abstract: | Sphingosine kinase (SK)-1 promotes endothelial cell (EC) survival through the cell junction molecule CD31 (platelet endothelial cell adhesion molecule-1). The integrin vβ3 is also essential for EC survival; inhibition of vβ3 ligation promotes apoptosis. Herein we demonstrate that under basal conditions, SK-1, vβ3, and CD31 exist as a heterotrimeric complex. Under conditions that affect EC survival such as loss of contact with the extracellular matrix or growth factor activation, more of this heterotrimeric complex forms. Overexpression studies demonstrate a requirement for SK-1 phosphorylation at serine 225 for increased heterotrimeric complex formation, activation of vβ3, and EC survival signals, including Bcl-X and nuclear factor-B pathways. Moreover, β3 integrin depletion confirmed the requirement for this heterotrimeric complex in SK-1-mediated EC survival. Thus, with vβ3 integrin being identifiable primarily on angiogenic ECs and SK-1 being highly expressed in tumors, targeting SK-1 may affect multiple survival pathways, and its inhibition may be highly efficacious in controlling pathological EC survival. |
Keywords: | Cells, Cultured Focal Adhesions Endothelial Cells Humans Phosphotransferases (Alcohol Group Acceptor) Integrin alphaVbeta3 Membrane Proteins Proto-Oncogene Proteins RNA, Small Interfering Apoptosis Cell Survival Apoptosis Regulatory Proteins Focal Adhesion Protein-Tyrosine Kinases Bcl-2-Like Protein 11 Platelet Endothelial Cell Adhesion Molecule-1 |
DOI: | 10.2353/ajpath.2009.090076 |
Published version: | http://dx.doi.org/10.2353/ajpath.2009.090076 |
Appears in Collections: | Aurora harvest 5 Molecular and Biomedical Science publications |
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