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PDGF induces a ROS and Src kinase‐dependent PKC‐delta Tyr‐311 phosphorylation promoting vascular smooth muscle cell growth and proliferation
Author(s) -
Frank Gerald D.,
Inagami Tadashi
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb16-a
Subject(s) - platelet derived growth factor receptor , rottlerin , phosphorylation , protein kinase c , microbiology and biotechnology , tyrosine phosphorylation , vascular smooth muscle , proto oncogene tyrosine protein kinase src , cell growth , tyrosine kinase , signal transduction , biology , chemistry , growth factor , endocrinology , biochemistry , receptor , smooth muscle
Key signaling likely converge at the level of PKC activation since it is one of the earliest signaling events induced by PDGF. However, still unclear is how PKCδ is specifically activated and its role in vascular remodeling. We recently showed that PKCδ is linked to activation of various tyrosine kinases in VSMCs. Here, we elucidate the activation mechanism of PKCδ by PDGF and the VSMC response underlying vascular remodeling. PDGF time‐and concentration‐dependently induced phosphorylation of PKCδat Tyr 311 in VSMCs. Maximum phosphorylation occurred at 5–10 min and 100–200 μg/ml. This phosphorylation was inhibited by the PDGF receptor inhibitor AG1295 and the general tyrosine kinase inhibitor genistein. Also, rottlerin, a selective PKCδ inhibitor inhibited phosphorylation. We found that a ROS scavenger NAC inhibited PDGF‐induced phosphorylation of PKCδ at Tyr 311 . Interestingly, PDGF‐induced phosphorylation of PKCδwas blocked by tyrosine kinase Src inhibitor PP2. PP3 control had no effect. To examine the role of PKCδ Tyr 311 phosphorylation on VSMC growth and proliferation by PDGF, we established a VSMC cell line overexpressing PKCδ wild‐type or PKCδ Y311F mutants by retrovirus infection. Results indicate that PDGF‐induced protein synthesis was enhanced in VSMCs expressing wild‐type compared to Y311F mutant cells. However, there was no proliferation in Y311F VSMCs whereas PP2 inhibited control VSMCs. These data show that PDGF induces a ROS and Src‐dependent PKCδ Tyr 311 phosphorylation that may promote cell growth and proliferation.