© 2000 American Heart Association, Inc.
Molecular Medicine |
Focal Adhesion Kinase Is Involved in Angiotensin II–Mediated Protein Synthesis in Cultured Vascular Smooth Muscle Cells
From The Cardiovascular Institute (G.G., D.M.E., A.M.S), Loyola University Chicago, Maywood, Ill, and Department of Physiology and Biophysics (P.A.L.), University of Alabama at Birmingham, Birmingham, Ala.
Correspondence to Allen M. Samarel, MD, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. E-mail asamare{at}lumc.edu
Abstract—The rate of vascular smooth muscle cell protein synthesis and cellular hypertrophy in response to angiotensin II (Ang II) is dependent on activation of protein tyrosine kinases (PTKs) and both the extracellular signal–regulated kinase (ERK) 1/2 and p70S6K pathways. One potential PTK that may regulate these signaling cascades is focal adhesion kinase (FAK), a nonreceptor PTK associated with focal adhesions. We used an actin depolymerizing agent, cytochalasin D (Cyt-D), and a replication-defective adenovirus encoding FAK-related nonkinase (FRNK), an inhibitor of FAK-dependent signaling, as tools to assess whether FAK was upstream of the ERK1/2 and/or the p70S6K pathways. Cyt-D reduced basal FAK phosphorylation and blocked Ang II–dependent FAK phosphorylation in a dose-dependent manner. Confocal microscopy indicated that Cyt-D induced actin filament disruption and FAK delocalization from focal adhesions. Cyt-D also reduced Ang II–induced ERK1/2 activation, but p70S6K activation was relatively unaffected. Cyt-D reduced basal protein synthetic rate and substantially reduced the Ang II–induced increase in protein synthesis. Similarly, FRNK overexpression blocked Ang II–induced FAK phosphorylation and ERK1/2 activation, but not p70S6K phosphorylation, and markedly inhibited protein synthesis. This is the first report to demonstrate that FAK is a critical component of the signal transduction pathways that mediate Ang II–induced ERK1/2 activation, c-fos induction, and enhanced protein synthesis in vascular smooth muscle cells.
Key Words: FRNK • adenovirus • cytochalasin D • p70S6 kinase • extracellular signal–regulated kinase
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