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Molecular and Cellular Biology, November 2003, p. 8058-8069, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8058-8069.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Akt Phosphorylation of Serine 21 on Pak1 Modulates Nck Binding and Cell Migration

Guo-Lei Zhou,1 Ya Zhuo,1 Charles C. King,2 Benjamin H. Fryer,1 Gary M. Bokoch,3 and Jeffrey Field1*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,1 Department of Pharmacology, University of California, San Diego, La Jolla, California 92093,2 Departments of Immunology and Cell Biology, Scripps Research Institute, La Jolla, California 920373

Received 31 March 2003/ Returned for modification 6 May 2003/ Accepted 13 August 2003

The p21-activated protein kinases (Paks) regulate cellular proliferation, differentiation, transformation, and survival through multiple downstream signals. Paks are activated directly by the small GTPases Rac and Cdc42 and several protein kinases including Akt and PDK-1. We found that Akt phosphorylated and modestly activated Pak1 in vitro. The major site phosphorylated by Akt on Pak1 mapped to serine 21, a site originally shown to be weakly autophosphorylated on Pak1 when Cdc42 or Rac activates it. A peptide derived from the region surrounding serine 21 was a substrate for Akt but not Pak1 in vitro, and Akt stimulated serine 21 phosphorylation on the full-length Pak1 much better than Rac did. The adaptor protein Nck binds Pak near serine 21, and its association is regulated by phosphorylation of this site. We found that either treatment of Pak1 in vitro with Akt or coexpression of constitutively active Akt with Pak1 reduced Nck binding to Pak1. In HeLa cells, green fluorescent protein-tagged Pak1 was concentrated at focal adhesions and was released when Akt was cotransfected. A peptide containing the Nck binding site of Pak1 fused to a portion of human immunodeficiency virus Tat to allow it to enter cells was used to test the functional importance of Nck/Pak binding in Akt-stimulated cell migration. This Tat-Nck peptide reduced Akt-stimulated cell migration. Together, these data suggest that Akt modulates the association of Pak with Nck to regulate cell migration.

* Corresponding author. Mailing address: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: (215) 898-1912. Fax: (215) 573-2236. E-mail: field{at}pharm.med.upenn.edu.

Molecular and Cellular Biology, November 2003, p. 8058-8069, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8058-8069.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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