期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 18, 页码 12712-12721出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.452383
关键词
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资金
- National Institutes of Health Grant [R01 HL062289]
- Fondazione Istituto Toscano Tumori
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Societa Italiana di Farmacologia (SIF)
Prostaglandin E-2 (PGE(2)) is regarded as the main mediator of inflammatory symptoms. In addition, it also plays an important role in tumor growth and angiogenesis. In this study, we examined the mechanism of PGE(2)-induced angiogenic response. We show that in the absence of proteoglycan syndecan-4 (Sdc4), PGE(2)-induced ERK activation is decreased significantly, as is endothelial cell migration and cord formation in a two-dimensional Matrigel assay. In vivo, PGE(2)-induced angiogenesis is reduced dramatically in Sdc4(-/-) mice. The mechanism was traced to Sdc4-dependent activation of protein kinase C alpha (PKC alpha). Transduction of an Sdc4 S183E mutant (a cytoplasmic domain mutation that blocks Sdc4-dependent PKC alpha activation) into Sdc4(-/-) endothelial cells was not able to rescue the loss of PGE(2)-induced ERK activation, whereas a transduction with full-length Sdc4 resulted in full rescue. Furthermore, PGE(2)-induced angiogenesis was also reduced in PKC alpha(-/-) mice. Taken together, these results demonstrate that PGE(2)-induced activation of angiogenesis is mediated via syndecan-4-dependent activation of PKC alpha.
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