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KMID : 0603519990040040173
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Journal of Korean Association of Cancer Prevention
1999 Volume.4 No. 4 p.173 ~ p.179
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Sphingosine 1-phosphate-induced Angiogenesis Involves Src Protein Kinases
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Lee Ok-Hee
Kim Kyu-Won
Kwon Young-Guen
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Abstract
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Several lines of clinical and preclinical evidences have suggested that platelets may importantly contribute to tumor-induced angiogenesis. We have recently reported that sphingosine 1-phosphate (S1P), which is abundantly stored in platelets and released upon platelet activation, induces angiogenesis through Gi protein-coupled receptors. In the present study, we further investigated the signaling pathways of mitogen activated protein kinases (MAPKs) stimulated by S1P in human umbilical vein endothelial cells (HUVECs). S1P rapidly induced extracellular signal-regulated kinases (ERKs) and p38 mitogen- activated protein kinase (p38 MAPK) activation in HUVECs. Notably, S1P-induced ERKs and p38 MAPK activation was almost completely inhibited by the phospholipase C (PLC) inhibitor U73122 but not affected by the phosphatidylinositol 3-kinase (PI-3K) inhibitor wortmannin. As a downstream of PLC, S1P-induced ERK activation was totally blocked by inhibition of intracellular Ca2+ mobilization by BAPTA- AM, a calcium chelator, but further stimulated by ionomycin. In contrast, the protein kinase C (PKC) inhibitor GF109203X had no effect. Thus, an increase in intracellular Ca2+ is closely involved in S1P-dependent signaling. Moreover, ERK activation by S1P was completely blocked by the calmodulin inhibitor W-7 but not by KN-93, a selective inhibitor of Ca2+/ calmodulin-dependent protein kinases. The Src tyrosine kinase inhibitor PP1 significantly reduced both S1P- and ionomycin-induced ERK activation. In addition, S1P-induced HUVEC migration was blocked by PP1 in a dose-dependent manner. Therefore, these results suggest that Src protein kinases activated by Ca2+/calmodulin signaling may be an important mediator of angiogenesis in response to S1P.
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KEYWORD
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Sphingosine 1-phosphate, Angiogenesis, ERK, p38 MAPK, Src
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