Sphingosine kinase-1 associates with integrin {alpha}V{beta}3 to mediate endothelial cell survival.

Abstract

Sphingosine kinase (SK)-1 promotes endothelial cell (EC) survival through the cell junction molecule CD31 (platelet endothelial cell adhesion molecule-1). The integrin alpha(v)beta(3) is also essential for EC survival; inhibition of alpha(v)beta(3) ligation promotes apoptosis. Herein we demonstrate that under basal conditions, SK-1, alpha(v)beta(3), 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 alpha(v)beta(3), and EC survival signals, including Bcl-X and nuclear factor-kappaB pathways. Moreover, beta(3) integrin depletion confirmed the requirement for this heterotrimeric complex in SK-1-mediated EC survival. Thus, with alpha(v)beta(3) 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.

• Authors: Jennifer R Gamble, Wai Y Sun, Xiaochun Li, Christopher N Hahn, Stuart M Pitson, Mathew A Vadas, Claudine S Bonder
• Journal: The American journal of pathology (Am J Pathol) Vol. 175 Issue 5 Pg. 2217-25 (Nov 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19815712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Integrin alphaVbeta3
• Membrane Proteins
• Platelet Endothelial Cell Adhesion Molecule-1
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Apoptosis (physiology)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Cell Survival (physiology)
• Cells, Cultured
• Endothelial Cells (cytology, physiology)
• Focal Adhesion Protein-Tyrosine Kinases (genetics, metabolism)
• Focal Adhesions (metabolism)
• Humans
• Integrin alphaVbeta3 (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (genetics, metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)