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(Circulation. 2001;104:1399.)
© 2001 American Heart Association, Inc.

Basic Science Reports

p160 Bcr Mediates Platelet-Derived Growth Factor Activation of Extracellular Signal-Regulated Kinase in Vascular Smooth Muscle Cells

Wenyi Che, MD, PhD; Jun-ichi Abe, MD, PhD; Masanori Yoshizumi, MD, PhD; Qunhua Huang, PhD; Michael Glassman, BS; Shinsuke Ohta, DDS, PhD; Matthew G. Melaragno, PhD; Veronica Poppa, PhD; Chen Yan, PhD; Nicole Lerner-Marmarosh, PhD; Changxi Zhang, PhD; Yun Wu, PhD; Ralph Arlinghaus, MD, PhD; Bradford C. Berk, MD, PhD

From the Center for Cardiovascular Research, University of Rochester, Rochester, NY (W.C., J.A., M.Y., Q.H., M.G., S.O., C.Y., N.L.-M., C.Z., B.C.B.); the Department of Molecular Pathology, M.D. Anderson Cancer Center, Houston, Tex (Y.W., R.A.); Merck & Co, Inc, Rochester, NY (M.G.M.); and the Department of Pathology, University of Washington, Seattle (V.P.).

Correspondence to Jun-ichi Abe, MD, PhD, Center for Cardiovascular Research, Box 679, 601 Elmwood Ave, Rochester, NY 14642. E-mail jun-ichi_abe{at}urmc.rochester.edu

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 pathway to ERK1/2 activation and DNA synthesis in rat aortic smooth muscle cells (RASMCs).

Methods and Results—— In RASMCs, platelet-derived growth factor-BB (PDGF) stimulated Bcr kinase activity, with a maximum at 1 minute. Because phosphatidylinositol 3'-kinase (PI3-K) is essential for Bcr/Abl leukemogenesis, we evaluated the role of mouse PDGF-ß-receptor binding sites for PI3-K (Y708, Y719) and for phospholipase C- (Y977, Y989) in PDGF-mediated Bcr kinase 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 downstream Elk1 transcription activation, wild-type (WT) and kinase-negative (KN) Bcr were transiently expressed in RASMCs. Bcr WT enhanced, whereas Bcr KN inhibited, PDGF-stimulated ERK1/2 and Elk1 transcriptional activity. Overexpression of Bcr also enhanced PDGF-induced Ras/Raf-1 activity and DNA synthesis, but this regulation is independent of the kinase activity of Bcr. Finally, we found that Bcr expression was increased in the neointimal layer after balloon injury of rat carotid artery.

Conclusions—— These results demonstrated the importance of Bcr in PDGF-mediated events, such as activation of Ras, Raf-1, ERK1/2, and Elk1, and stimulation of DNA synthesis.

Key Words: aorta • cardiovascular diseases • carotid arteries • cells • signal transduction

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