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Published 21 July 2003. doi:10.1083/jcb.200212141
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© The Rockefeller University Press, 0021-9525/2003/7/281 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 281-291

Article

PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation



Jill K. Slack-Davis1, Scott T. Eblen1, Maja Zecevic1, Scott A. Boerner1, Adel Tarcsafalvi1, H. Bruce Diaz3,5, Mark S. Marshall3,4,5, Michael J. Weber1,2, J. Thomas Parsons1,2 and Andrew D. Catling1

1 Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908
2 The Cancer Center, University of Virginia Health System, Charlottesville, VA 22908
3 Department of Medicine and Biochemistry, Indiana University School of Medicine, Indianapolis, IN 46202
4 Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202
5 Lilly Research Laboratories, Indianapolis, IN 46285

Address correspondence to J. Thomas Parsons, Dept. of Microbiology, Box 800734, University of Virginia Health System, Charlottesville, VA 22908-0734. Tel.: (434) 924-5395. Fax: (434) 982-1071. E-mail: jtp{at}virginia.edu; or Andrew D. Catling at his present address Dept. of Pharmacology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112-1393. Tel.: (504) 568-2222. Fax: (504) 568-2361. E-mail: acatli{at}lsuhsc.edu

Activation of the Ras–MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane–proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf–MEK1–MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK.

Key Words: integrin; adhesion; focal adhesion kinase; Src; extracellular matrix

The online version of this article includes supplemental material.

M. Zecevic's present address is Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 309, MSC 7361, Rockville, MD 20852.

* Abbreviations used in this paper: FN, fibronectin; MEK, MAPK kinase; MEKK, MEK kinase; PAK, p21-activated kinase; PI3K, phosphoinositide 3-kinase.


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