The p21-activated protein kinase gamma-PAK is activated under conditions of hyperosmotic stress, by low levels of ionizing radiation, by DNA-damaging drugs, and by sphingosine. In addition, gamma-PAK is constitutively activated in early apoptosis via cleavage into two fragments by caspase 3 (CPP32). Gamma-PAK appears to function through phosphorylation of a number of different substrates. Gamma-PAK induces cytostasis as shown by injection of active gamma-PAK into frog oocytes, and transient transfection and expression of gamma-PAK in mammalian cells reduces cell viability. Conditions of stress inhibit cell division, reduce and alter the specificity of transcription and translation, and cause changes in metabolism. The focus of these studies are as follows. 1) The cytostatic properties of gamma-PAK will be examined in mammalian cell culture by identification of the upstream activators of gamma-PAK under different stress conditions and their role in activation of the protein kinase will be determined. The requirements for translocation and activation of gamma-PAK to achieve cytostasis and the role of protein:protein interactions in targeting the protein kinase will be examined by expression of site-directed mutants in mammalian cells. 2) Regulation of gamma-PAK activity by autophosphorylation and by phosphorylation by other protein kinases will be analyzed in vivo and in vitro. Proteins associated with endogenously active gamma-PAK will be identified and the effects of phosphorylation of the proteins by gamma-PAK will be determined. 3) A comparison of the substrate specificity between alpha-PAK and gamma-PAK will be determined using peptide substrates. Protein substrates for gamma-PAK will be identified, the sites of phosphorylation in substrates of interest will be determined, and the effects of phosphorylation on substrate activity will be analyzed. 4) Prepare protein for a collaborative effort to obtain structures of the regulatory (p27) and catalytic domain (p34) and of the gamma-PAK holoenzyme by x-ray crystallography.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Physiological Chemistry Study Section (PC)
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Ikeda, Richard A
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University of California Riverside
Schools of Earth Sciences/Natur
United States
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Hsu, Yuan-Hao; Traugh, Jolinda A (2011) Amide hydrogen/deuterium exchange & MALDI-TOF mass spectrometry analysis of Pak2 activation. J Vis Exp :e3602
Hsu, Yuan-Hao; Traugh, Jolinda A (2010) Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis. PLoS One 5:e9455
Hsu, Yuan-Hao; Johnson, David A; Traugh, Jolinda A (2008) Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange. J Biol Chem 283:36397-405
Jung, Jin-Hun; Pendergast, Ann Marie; Zipfel, Patricia A et al. (2008) Phosphorylation of c-Abl by protein kinase Pak2 regulates differential binding of ABI2 and CRK. Biochemistry 47:1094-104
Ling, Jun; Morley, Simon J; Traugh, Jolinda A (2005) Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. EMBO J 24:4094-105
Jung, Jin-Hun; Traugh, Jolinda A (2005) Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141. J Biol Chem 280:40025-31
Miah, S M Shahjahan; Sada, Kiyonao; Tuazon, Polygena T et al. (2004) Activation of Syk protein tyrosine kinase in response to osmotic stress requires interaction with p21-activated protein kinase Pak2/gamma-PAK. Mol Cell Biol 24:71-83
Orton, Kevin C; Ling, Jun; Waskiewicz, Andrew J et al. (2004) Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem 279:38649-57
Huang, Zhongdong; Ling, Jun; Traugh, Jolinda A (2003) Localization of p21-activated protein kinase gamma-PAK/Pak2 in the endoplasmic reticulum is required for induction of cytostasis. J Biol Chem 278:13101-9
Tuazon, Polygena T; Lorenson, Mary Y; Walker, Ameae M et al. (2002) p21-activated protein kinase gamma-PAK in pituitary secretory granules phosphorylates prolactin. FEBS Lett 515:84-8

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