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Mol. Cell. Biol. 22 (17): 6023-6033

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes

Scott T. Eblen,* Jill K. Slack, Michael J. Weber, and Andrew D. Catling*

Department of Microbiology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908

Received for publication 11 February 2002. Revision received 18 March 2002. Accepted for publication 3 June 2002.

Abstract: Utilizing mutants of extracellular signal-regulated kinase 2 (ERK2) that are defective for intrinsic mitogen-activated protein kinase or ERK kinase (MEK) binding, we have identified a convergent signaling pathway that facilitates regulated MEK-ERK association and ERK activation. ERK2-{Delta}19-25 mutants defective in MEK binding could be phosphorylated in response to mitogens; however, signaling from the Raf-MEK pathway alone was insufficient to stimulate their phosphorylation in COS-1 cells. Phosphorylation of ERK2-{Delta}19-25 but not of wild-type ERK2 in response to Ras V12 was greatly inhibited by dominant-negative Rac. Activated forms of Rac and Cdc42 could enhance the association of wild-type ERK2 with MEK1 but not with MEK2 in serum-starved adherent cells. This effect was p21-activated kinase (PAK) dependent and required the putative PAK phosphorylation sites T292 and S298 of MEK1. In detached cells placed in suspension, ERK2 was complexed with MEK2 but not with MEK1. However, upon replating of cells onto a fibronectin matrix, there was a substantial induction of MEK1-ERK2 association and ERK activation, both of which could be inhibited by dominant-negative PAK1. These data show that Rac facilitates the assembly of a mitogen-activated protein kinase signaling complex required for ERK activation and that this facilitative signaling pathway is active during adhesion to the extracellular matrix. These findings reveal a novel mechanism by which adhesion and growth factor signals are integrated during ERK activation.

* Corresponding author. Mailing address: Department of Microbiology, P.O. Box 800734, Rm. 216 Jordan Hall, University of Virginia, Charlottesville, VA 22908. Phone: (434) 924-8710. Fax: (434) 982-0689. E-mail for Scott T. Eblen: E-mail for Andrew D. Catling: adc2a{at}

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