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

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, H₂O₂ 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 vascular diseases, we have examined a signal transduction cascade involved in H₂O₂-induced platelet-derived growth factor receptor activation in vascular smooth muscle cells. We found that H₂O₂ induced a ligand-independent phosphorylation of the platelet-derived growth factor-β receptor at Tyr¹⁰²¹, a phospholipase C-γ binding site, involving the requirement of protein kinase C-δ and c-Src that is distinct from a ligand-dependent autophosphorylation. Also, H₂O₂ induced the association of protein kinase C-δ with the platelet-derived growth factor-β 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.