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Molecular and Cellular Biology, March 2004, p. 2308-2317, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2308-2317.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion

Scott T. Eblen,* Jill K. Slack-Davis, Adel Tarcsafalvi, J. Thomas Parsons, Michael J. Weber, and Andrew D. Catling{dagger}

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

Received 11 November 2003/ Accepted 17 December 2003

Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.

* 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: ste4n{at}virginia.edu.

{dagger} Present address: Department of Pharmacology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70115.

Molecular and Cellular Biology, March 2004, p. 2308-2317, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2308-2317.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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