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Molecular and Cellular Biology, March 2008, p. 1679-1687, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.00898-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Protein Kinase A-Dependent Phosphorylation Modulates β1Pix Guanine Nucleotide Exchange Factor Activity through 14-3-3β Binding{triangledown}

Ahmed Chahdi and Andrey Sorokin*

Division of Nephrology and Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Received 21 May 2007/ Returned for modification 12 July 2007/ Accepted 11 December 2007

β1Pix is a guanine nucleotide exchange factor (GEF) for the small GTPases Rac and Cdc42 which has been shown to mediate signaling pathways leading to cytoskeletal reorganization. In the present study, we show that the basal association between endogenous βPix and endogenous 14-3-3β was increased after forskolin stimulation and significantly inhibited by protein kinase A inhibitor. However, forskolin stimulation failed to increase the interaction between 14-3-3β and a β1Pix mutant that is insensitive to protein kinase A phosphorylation, β1Pix(S516A, T526A). We present evidence indicating that forskolin-induced binding of 14-3-3β to β1Pix results in inhibition of Rac1 GTP loading in 293 cells and in vitro. Furthermore, we show that deletion of 10 amino acid residues within the leucine zipper domain is sufficient to block β1Pix homodimerization and 14-3-3β binding and modulates β1Pix-GEF activity. These residues also play a crucial role in β1Pix intracellular localization. These results indicate that 14-3-3β negatively affects the GEF activity of dimeric β1Pix only. Altogether, these results provide a mechanistic insight into the role of 14-3-3β in modulating β1Pix-GEF activity.

* Corresponding author. Mailing address: Division of Nephrology and Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Phone: (414) 456-4438. Fax: (414) 456-6515. E-mail: sorokin{at}mcw.edu

{triangledown} Published ahead of print on 26 December 2007.

Molecular and Cellular Biology, March 2008, p. 1679-1687, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.00898-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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