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Molecular and Cellular Biology, May 2005, p. 3726-3736, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3726-3736.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

p21-Activated Kinase 1 Regulates Microtubule Dynamics by Phosphorylating Tubulin Cofactor B

Ratna K. Vadlamudi,1 Christopher J. Barnes,1 Suresh Rayala,1 Feng Li,1 Seetharaman Balasenthil,1 Stevan Marcus,2 Holly V. Goodson,3 Aysegul A. Sahin,4 and Rakesh Kumar1*

Departments of Molecular and Cellular Oncology,1 Molecular Genetics,2 Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas,4 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana3

Received 18 October 2004/ Returned for modification 26 November 2004/ Accepted 27 January 2005

p21-activated kinase 1 (Pak1) induces cytoskeleton reorganization in part by regulating microtubule dynamics through an elusive mechanism. Using a yeast two-hybrid screen, we identified tubulin cofactor B (TCoB) (a cofactor in the assembly of the {alpha}/ß-tubulin heterodimers) as an interacting substrate of Pak1. Pak1 directly phosphorylated TCoB in vitro and in vivo on serines 65 and 128 and colocalized with TCoB on newly polymerized microtubules and on centrosomes. TCoB interacted with the GTPase-binding domain of Pak1 and activated Pak1 in vitro and in vivo. In contrast to wild-type TCoB, an S65A, S128A double mutant and knock-down of the endogenous TCoB or Pak1 reduced microtubule polymerization, suggesting that Pak1 phosphorylation is necessary for normal TCoB function. Overexpression of TCoB dramatically increased the number of {gamma}-tubulin-containing microtubule-organizing centers, a phenotype reminiscent of cells overexpressing Pak1. TCoB was overexpressed and phosphorylated in breast tumors. These findings reveal a novel role for TCoB and Pak1 in regulating microtubule dynamics.

* Corresponding author. Mailing address: Box 108, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 745-3558. Fax: (713) 745-3792. E-mail: rkumar{at}mdanderson.org.

Molecular and Cellular Biology, May 2005, p. 3726-3736, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3726-3736.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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