Sphingosine kinase-1 associates with integrin {alpha}V{beta}3 to mediate endothelial cell survival.
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.
Gamble
Jennifer R
JR
Centenary Institute for Cancer Medicine and Cell Biology, University of Sydney, Australia.
Sun
Wai Y
WY
Li
Xiaochun
X
Hahn
Christopher N
CN
Pitson
Stuart M
SM
Vadas
Mathew A
MA
Bonder
Claudine S
CS
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000099157:Sphingosine Kinase; C000606775:BCL2L11 protein, human