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J. Biol. Chem. 278 (33): 31111-31117

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Initiation and Transduction of Stretch-induced RhoA and Rac1 Activation through Caveolae

CYTOSKELETAL REGULATION OF ERK TRANSLOCATION*

Shuji Kawamura, Shigeki Miyamoto, and Joan Heller Brown {ddagger}

Department of Pharmacology, University of California, San Diego, La Jolla, California 92093

Abstract: The Rho family small GTPases play a crucial role in mediating cellular responses to stretch. However, it remains unclear how force is transduced to Rho signaling pathways. We investigated the effect of stretch on the activation and caveolar localization of RhoA and Rac1 in neonatal rat cardiomyocytes. In unstretched cardiomyocytes, RhoA and Rac1 were detected in both caveolar and non-caveolar fractions as assessed using detergent-free floatation analysis. Stretching myocytes for 4 min activated RhoA and Rac1. By 15 min of stretch, RhoA and Rac1 had dissociated from caveolae, and there was decreased coprecipitation of RhoA and Rac1 with caveolin-3. To determine whether compartmentation of RhoA and Rac1 within caveolae was necessary for stretch signaling, we disrupted caveolae with methyl {beta}-cyclodextrin (M{beta}CD). Treatment with 5 mM M{beta}CD for 1 h dissociated both RhoA and Rac1 from caveolae. Under this condition, stretch failed to activate RhoA or Rac1. Stretch-induced actin cytoskeletal organization was concomitantly impaired. Interestingly the ability of stretch to activate extracellular signal-regulated kinase (ERK) was unaffected by M{beta}CD treatment, but ERK translocation to the nucleus was impaired. Stretch-induced hypertrophy was also inhibited. Actin cytoskeletal disruption with cytochalasin-D also prevented stretch from increasing nuclear ERK, whereas actin polymerization with jasplakinolide restored nuclear translocation of activated ERK in the presence of M{beta}CD. We suggest that activation of RhoA or Rac1, localized in a caveolar compartment, is essential for sensing externally applied force and transducing this signal to the actin cytoskeleton and ERK translocation.


Received for publication January 22, 2003. Revision received May 14, 2003.

* This work was supported by National Institutes of Health Grants HL28143 and HL46345 (to J. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} To whom correspondence should be addressed: Dept. of Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0636. Tel.: 858-534-2595; Fax: 858-534-4337; E-mail: jhbrown{at}ucsd.edu.


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