title: Protein kinase CK2 phosphorylates and activates p21-activated kinase 1.
abstract: Activation of the p21-activated kinase 1 (PAK1) is achieved through a conformational change that converts an inactive PAK1 dimer to an active monomer. In this paper, we show that this change is necessary but not sufficient to activate PAK1 and that it is, rather, required for CK2-dependent PAK1(S223) phosphorylation that converts a monomeric PAK1 into a catalytically active form. This phosphorylation appears to be essential for autophosphorylation at specific residues and overall activity of PAK1. A phosphomimetic mutation (S223E) bypasses the requirement for GTPases in PAK1 activation, whereas the constitutive activity of the PAK1 mutant (PAK1(H83,86L)), postulated to mimic GTPase-induced structural changes, is abolished by inhibition of S223 phosphorylation. Thus, S223 is likely accessible to CK2 upon conformational changes of PAK1 induced by GTPase-dependent and GTPase-independent stimuli, suggesting that S223 phosphorylation may play a key role in the final step of the PAK1 activation process. The physiological significance of this phosphorylation is reinforced by the observations that CK2 is responsible for epidermal growth factor-induced PAK1 activation and that inhibition of S223 phosphorylation abrogates PAK1-mediated malignant transformation of prostate epithelial cells. Taken together, these findings identify CK2 as an upstream activating kinase of PAK1, providing a novel mechanism for PAK1 activation.
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University Medical Center, Washington, DC 20037.
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Shin
authors.forename: Yong-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D015153:Blotting, Western; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011467:Prostate / Q000473:pathology; D015203:Reproducibility of Results; D054462:p21-Activated Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010768:Phosphoserine; D004815:Epidermal Growth Factor; D047390:Casein Kinase II; D054462:p21-Activated Kinases