Ligand-independenttrans-Activation of the Platelet-derived Growth Factor Receptor by Reactive Oxygen Species Requires Protein Kinase C-δ and c-Src

Shuichi Saito, Gerald D. Frank, Mizuo Mifune, Motoi Ohba, Hirotoshi Utsunomiya, Evangeline D. Motley, Tadashi Inagami, Satoru Eguchi
2002 Journal of Biological Chemistry  
Reactive oxygen species are involved in the mitogenic signal transduction cascades initiated by several growth factors and play a critical role in mediating cardiovascular diseases. Interestingly, H 2 O 2 induces tyrosine phosphorylation and trans-activation of the platelet-derived growth factor receptor and the epidermal growth factor receptor in many cell lines including vascular smooth muscle cells. To investigate the molecular mechanism by which reactive oxygen species contribute to
more » ... diseases, we have examined a signal transduction cascade involved in H 2 O 2 -induced plateletderived growth factor receptor activation in vascular smooth muscle cells. We found that H 2 O 2 induced a ligand-independent phosphorylation of the plateletderived growth factor-␤ receptor at Tyr 1021 , a phospholipase C-␥ binding site, involving the requirement of protein kinase C-␦ and c-Src that is distinct from a liganddependent autophosphorylation. Also, H 2 O 2 induced the association of protein kinase C-␦ with the plateletderived growth factor-␤ receptor and c-Src in vascular smooth muscle cells. These findings will provide new mechanistic insights by which enhanced reactive oxygen species production in vascular smooth muscle cells induces unique alleys of signal transduction distinct from those induced by endogenous ligands leading to an abnormal vascular remodeling process.
doi:10.1074/jbc.m208332200 pmid:12226102 fatcat:t2bwa7msevbgfakwkh4mhp4ruu