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Papers In Press, published online ahead of print January 30, 2003
University of California, Riverside, Riverside, CA 92521
Corresponding Author: jolinda.traugh{at}ucr.edu
The intracellular localization and physiological functions of the p21-activated protein kinase
J. Biol. Chem, 10.1074/jbc.M212557200
Submitted on December 10, 2002
Revised on January 30, 2003
Accepted on January 29, 2003
Localization of p21-activated protein kinase
-PAK/Pak2 in the endoplasmic reticulum is required for induction of cytostasis
-PAK have been examined in HEK 293T and COS-7 cells. At 1-3 days post-transfection, cell division is inhibited by expression of wild type (WT) -PAK and the mutant S490A, while cells expressing S490D and the inactive mutants K278R and T402A are growing exponentially, indicating a role for -PAK in the induction of cytostasis. WT--PAK and S490A are localized in a region surrounding the nucleus identified as the endoplasmic reticulum (ER), as determined by immunofluorescence, while K278R, T402A and S490D lack localization. As shown by sucrose density gradient centrifugation, WT--PAK, S490A and endogenous -PAK are distributed between the high density (ER-associated), intermediate density, and low density fractions, while the mutants that do not inhibit cell division are present only as soluble enzyme. The amount of endogenous -PAK associated with the particulate fractions is increased 4-fold when cell division is inhibited by ionizing radiation. -PAK in the ER and intermediate density fractions has high specific activity and is active, while the soluble form of -PAK has low activity and is activatable. The importance of localization of -PAK is supported by data with the C-terminal mutants S490D and 
488; these mutants have high levels of protein kinase activity, but do not induce cytostasis and are not bound to the ER. A model for the induction of cytostasis by -PAK through targeting of -PAK to the ER is presented in which -PAK activity and Ser 490 are implicated in the regulation of cytostasis.
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