© 1999 American Heart Association, Inc.
Original Contribution |
Vascular Endothelial Growth Factor Induces Activation and Subcellular Translocation of Focal Adhesion Kinase (p125FAK) in Cultured Rat Cardiac Myocytes
From the Departments of Cardiovascular Medicine (N.T., Y.S., K.T., T.K., Y.Y.) and Nephrology and Endocrinology (E.N.), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo; Institute for Adult Diseases (N.T., Y.S.), Asahi Life Foundation, Shinjuku-ku, Tokyo; Department of Immunology (Y.S.), School of Medicine, Juntendo University, Bunkyo-ku, Tokyo; and Department of Molecular Biology (H.S.), Osaka BioScience Institute, Suita, Osaka, Japan.
Correspondence to Naoyuki Takahashi, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail takan-tky{at}umin.ac.jp
Abstract—Vascular endothelial growth factor (VEGF) has been proposed to be among the candidate factors with the most potential to play a role in ischemia-induced collateral vessel formation. Recently, we found that VEGF activated the mitogen-activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate how VEGF affects adhesive interaction of cardiac myocytes with the extracellular matrix (ECM), one of the important cell functions, we investigated the molecular mechanism of activation of focal adhesion-related proteins, especially focal adhesion kinase (p125FAK), in cultured rat cardiac myocytes. We found that the 2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation. VEGF induced tyrosine phosphorylation and activation of p125FAK as well as tyrosine phosphorylation of paxillin; this was accompanied by subcellular translocation of p125FAK from perinuclear sites to the focal adhesions. This VEGF-induced activation of p125FAK was inhibited partially by the tyrosine kinase inhibitors genistein and tyrphostin. Activation of p125FAK was accompanied by its increased association with adapter proteins GRB2, Shc, and nonreceptor type tyrosine kinase p60c-src. Furthermore, we confirmed that VEGF induced a significant increase in adhesive interaction between cardiac myocytes and ECM using an electric cell-substrate impedance sensor. These results strongly suggest that p125FAK is one of the most important components in VEGF-induced signaling in cardiac myocytes, playing a critical role in adhesive interaction between cardiac myocytes and ECM.
Key Words: signal transduction • growth substance • cardiac myocyte • cell adhesion
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