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Molecular and Cellular Biology, June 2005, p. 4466-4475, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4466-4475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Raf-1 Serine 338 Phosphorylation Plays a Key Role in Adhesion-Dependent Activation of Extracellular Signal-Regulated Kinase by Epidermal Growth Factor{dagger}

Matthew L. Edin and Rudy L. Juliano*

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365

Received 11 February 2005/ Accepted 4 March 2005

Activation of the extracellular signal-regulated kinase (ERK) 1/2 cascade by polypeptide growth factors is tightly coupled to adhesion to extracellular matrix in nontransformed cells. Raf-1, the initial kinase in this cascade, is intricately regulated by phosphorylation, localization, and molecular interactions. We investigated the complex interactions between Raf-1, protein kinase A (PKA), and p21-activated kinase (PAK) to determine their roles in the adhesion dependence of signaling from epidermal growth factor (EGF) to ERK. We conclude that Raf-1 phosphorylation on serine 338 (S338) is a critical step that is inhibited in suspended cells. Restoration of phosphorylation at S338, either by expression of highly active PAK or by expression of an S338 phospho-mimetic Raf-1 mutation, led to a partial rescue of ERK activation in suspended cells. Raf-1 inhibition in suspension was not due to excessive negative regulation on inhibitory sites S43 and S259, as these serines were largely dephosphorylated in suspended cells. Finally, strong phosphorylation of Raf-1 S338 provided resistance to PKA-mediated inhibition of ERK activation. Phosphorylation at Raf-1 S43 and S259 by PKA only weakly inhibited EGF activation of Raf-1 and ERK when cells maintained high Raf-1 S338 phosphorylation.

* Corresponding author. Mailing address: Department of Pharmacology, University of North Carolina, Chapel Hill, 1017 Mary Ellen Jones Building, CB 7365, Chapel Hill, NC 27599-7365. Phone: (919) 966-4383. Fax: (919) 966-5640. E-mail: arjay{at}med.unc.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2005, p. 4466-4475, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4466-4475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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