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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

PI3K activation is required for PMA-directed activation of cSrc by AFAP-110

¹The Mary Babb Randolph Cancer Center and the Department of Microbiology, Immunology, and Cell Biology, West Virginia University; and ²Department of Neurobiology and Anatomy, School of Medicine, West Virginia University, Morgantown, West Virginia; and ³Department of Biology, University of West Georgia, Carrolton, Georgia

Submitted 10 October 2006 ; accepted in final form 20 February 2007

Activation of PKC will induce the cSrc binding partner AFAP-110 to colocalize with and activate cSrc. The ability of AFAP-110 to colocalize with cSrc is contingent on the integrity of the amino-terminal pleckstrin homology (PH1) domain, while the ability to activate cSrc is dependent on the integrity of its SH3 binding motif, which engages the cSrc SH3 domain. The outcome of AFAP-110-directed cSrc activation is a change in actin filament integrity and the formation of podosomes. Here, we address what cellular signals promote AFAP-110 to colocalize with and activate cSrc, in response to PKC activation or PMA treatment. Because PH domain integrity in AFAP-110 is required for colocalization, and PH domains are known to interact with both protein and lipid binding partners, we sought to determine whether phosphatidylinositol 3-kinase (PI3K) activation played a role in PMA-induced colocalization between AFAP-110 and cSrc. We show that PMA treatment is able to direct activation of PI3K. Treatment of mouse embryo fibroblast with PI3K inhibitors blocked PMA-directed colocalization between AFAP-110 and cSrc and subsequent cSrc activation. PMA also was unable to induce colocalization or cSrc activation in cells that lacked the p85 and - regulatory subunits of PI3K. This signaling pathway was required for migration in a wound healing assay. Cells that were null for cSrc or the p85 regulatory subunits or expressed a dominant-negative AFAP-110 also displayed a reduction in migration. Thus PI3K activity is required for PMA-induced colocalization between AFAP-110 and cSrc and subsequent cSrc activation, and this signaling pathway promotes cell migration.

phorbol 12-myristate 13-acetate; Src; protein kinase C; AFAP-110; phosphatidylinositol 3-kinase; pleckstrin homology domain

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