Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141

doi:10.1074/jbc.M509075200

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Papers In Press, published online ahead of print October 4, 2005
J. Biol. Chem, 10.1074/jbc.M509075200
Submitted on August 17, 2005
Revised on September 28, 2005
Accepted on October 4, 2005

Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141

Jin-Hun Jung and Jolinda A. Traugh

Department of Biochemistry, University of California, Riverside, Riverside, CA 92521

Corresponding Author: jolinda.traugh{at}ucr.edu

Pak2, a member of the p21-activated protein kinase (PAK) family, is activated in response to a variety of stresses, and is directly involved in the induction of cytostasis. At the molecular level, Pak2 binds Cdc42(GTP), translocating Pak2 to the endoplasmic reticulum, where it is autophosphorylated and activated. Pak2 is autophosphorylated at eight sites; Ser141 and Ser165 in the regulatory domain and Thr402 in the activation loop are identified as key sites in activation of the protein kinase. The function of phosphorylation of Ser141 and Ser165 on the activation is analyzed with wild type (WT) and mutants of Pak2. With S141A, the level of autophosphorylation is reduced to 65%, as compared to WT and S141D, with a concomitant 45% reduction in substrate phosphorylation, indicating phosphorylation at Ser141 is required for optimal activity. Autophosphorylation inhibits the interaction between WT Pak2 and Cdc42(GTP). In 293T cells, WT Pak2, S141A and S141D form a stable complex with the constitutively active mutant Cdc42 L61, but not with the dominant-negative Cdc42 N17. As shown in GST pull-down assays, S141A binds to Cdc42(GTP) at a 6-fold higher level than that of S141D. In contrast, the S165A and S165D mutants have no effect on autophosphorylation, on binding to Cdc42, or on activation of Pak2. In summary, autophosphorylation of Ser141 is required for activation of Pak2 and down-regulates the interaction of Pak2 with Cdc42. A model is proposed suggesting that binding of Cdc42 localizes Pak2 to the ER, where autophosphorylation alters association of the two proteins.

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