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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Survival / physiology*
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Cells, Cultured
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Endothelial Cells / cytology
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Endothelial Cells / physiology*
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Focal Adhesion Protein-Tyrosine Kinases / genetics
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Focal Adhesions / metabolism
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Humans
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Integrin alphaVbeta3 / genetics
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Integrin alphaVbeta3 / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Integrin alphaVbeta3
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Membrane Proteins
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Platelet Endothelial Cell Adhesion Molecule-1
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Focal Adhesion Protein-Tyrosine Kinases