HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/C807    most recent 00436.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Mifune, M. Articles by Eguchi, S. Search for Related Content PubMed PubMed Citation Articles by Mifune, M. Articles by Eguchi, S.

RECEPTORS AND SIGNAL TRANSDUCTION

Signal transduction of betacellulin in growth and migration of vascular smooth muscle cells

¹Cardiovascular Research Center and ⁶Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; ²Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; ³Department of Pathology, Wakayama Medical University, Wakayama 641-8509, Japan; ⁴Pacific Northwest Research Institute, Seattle 98112; and ⁵Department of Medicine, University of Washington, Seattle, Washington 98195

Submitted 9 October 2003 ; accepted in final form 20 May 2004

Epidermal growth factor (EGF) family ligands have been implicated in cardiovascular diseases because of their enhanced expression in vascular lesions and their promoting effects on growth and migration of vascular smooth muscle cells (VSMCs). Betacellulin (BTC), a novel EGF family ligand, has been shown to be expressed in atherosclerotic lesions and to be a potent growth factor of VSMCs. However, the molecular mechanisms downstream of BTC involved in mediating vascular remodeling remain largely unknown. Therefore, the aim of this study was to examine the effects of BTC on signal transduction, growth, and migration in VSMCs. We found that BTC stimulated phosphorylation of EGF receptor (EGFR) at Tyr1068, which was completely blocked by an EGFR kinase inhibitor, AG-1478. BTC also phosphorylated ErbB2 at Tyr877, Tyr1112, and Tyr1248 and induced association of ErbB2 with EGFR, suggesting their heterodimerization in VSMCs. In postreceptor signal transduction, BTC stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and p38 mitogen-activated protein kinase (MAPK). Moreover, BTC stimulated proliferation and migration of VSMCs. ERK and Akt inhibitors suppressed migration markedly and proliferation partially, whereas the p38 inhibitor suppressed migration partially but not proliferation. In addition, we found the presence of endogenous BTC in conditioned medium of VSMCs and an increase of BTC on angiotensin II stimulation. In summary, BTC promotes growth and migration of VSMCs through activation of EGFR, ErbB2, and downstream serine/threonine kinases. Together with the expression and processing of endogenous BTC in VSMCs, our results suggest a critical involvement of BTC in vascular remodeling.

epidermal growth factor receptors; ErbB2; migration; signal transduction

This article has been cited by other articles:

				H. Oster and M. Leitges Protein Kinase C {alpha} but not PKC{zeta} Suppresses Intestinal Tumor Formation in ApcMin/+ Mice. Cancer Res., July 15, 2006; 66(14): 6955 - 6963. [Abstract] [Full Text] [PDF]

				Y. Tian, S. E. Kelemen, and M. V. Autieri Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1083 - C1091. [Abstract] [Full Text] [PDF]