p160 Bcr mediates platelet-derived growth factor activation of extracellular signal-regulated kinase in vascular smooth muscle cells

Background-The human Bcr gene was originally identified by its presence in the chimeric Bcr/Abl oncogene, which is causative for chronic myeloblastic leukemia. Because Bcr encodes a serine/threonine protein kinase, we studied its kinase activity and determined the role of Bcr in the PDGF signaling p athway to ERK1/2 activation and DNA synthesis in rat aortic smooth muscle c ells (RASMCs). Methods and Results-In RASMCs, platelet-derived growth factor-BB (PDGF) sti mulated Bcr kinase activity, with a maximum at 1 minute. Because phosphatid ylinositol 3 ' -kinase (P13-K) is essential for Bcr/Abl leukemogenesis, we evaluated the role of mouse PDGF-beta -receptor binding sites for P13-K (Y7 08, Y719) and for phospholipase C-gamma (Y977, Y989) in PDGF-mediated Bcr k inase activation. The mutant PDGF receptor Y708F/Y719F but not Y977F/Y989F showed significantly reduced Bcr kinase activity. To determine the role of Bcr in PDGF-mediated signal transduction events leading to ERK1/2 and its d ownstream Elk1 transcription activation, wild-type (WT) and kinase-negative (KN) Bcr were transiently expressed in RASMCs. Bcr WT enhanced, whereas Bc r KN inhibited, PDGF-stimulated ERK1/2 and Elk1 transcriptional activity. O verexpression of Bcr also enhanced PDGF-induced Ras/Raf-1 activity and DNA synthesis, but this regulation is independent of the kinase activity of Ben Finally, we found that Bcr expression was increased in the neointimal laye r after balloon injury of rat carotid artery. Conclusions-These results demonstrated the importance of Bcr in PDGF-mediat ed events, such as activation of Ras, Raf-1, ERK1/2, and Elk1, and stimulat ion of DNA synthesis.