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Molecular and Cellular Biology, June 2003, p. 4283-4294, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4283-4294.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of Rho Kinase and Actin Stress Fibers on Sustained Extracellular Signal-Regulated Kinase Activity and Activation of G1 Phase Cyclin-Dependent Kinases

Kristin Roovers and Richard K. Assoian*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

Received 17 December 2002/ Returned for modification 27 January 2003/ Accepted 18 March 2003

We recently reported that Rho kinase is required for sustained ERK signaling and the consequent mid-G1 phase induction of cyclin D1 in fibroblasts. The results presented here indicate that these Rho kinase effects are mediated by the formation of stress fibers and the consequent clustering of {alpha}5ß1 integrin. Mechanistically, {alpha}5ß1 signaling and stress fiber formation allowed for the sustained activation of MEK, and this effect was mediated upstream of Ras-GTP loading. Interestingly, disruption of stress fibers with ML-7 led to G1 phase arrest while comparable disruption of stress fibers with Y27632 (an inhibitor of Rho kinase) or dominant-negative Rho kinase led to a more rapid progression through G1 phase. Inhibition of either MLCK or Rho kinase blocked sustained ERK signaling, but only Rho kinase inhibition allowed for the induction of cyclin D1 and activation of cdk4 via Rac/Cdc42. The levels of cyclin E, cdk2, and their major inhibitors, p21cip1 and p27kip1, were not affected by inhibition of MLCK or Rho kinase. Overall, our results indicate that Rho kinase-dependent stress fiber formation is required for sustained activation of the MEK/ERK pathway and the mid-G1 phase induction of cyclin D1, but not for other aspects of cdk4 or cdk2 activation. They also emphasize that G1 phase cell cycle progression in fibroblasts does not require stress fibers if Rac/Cdc42 signaling is allowed to induce cyclin D1.

* Corresponding author. Mailing address: Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 167 Johnson Pavilion, Philadelphia, PA 19104-6084. Phone: (215) 898-7157. Fax: (215) 573-5656. E-mail: rka{at}pharm.med.upenn.edu.

Molecular and Cellular Biology, June 2003, p. 4283-4294, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4283-4294.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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