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Molecular and Cellular Biology, January 2004, p. 71-83, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.71-83.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of Syk Protein Tyrosine Kinase in Response to Osmotic Stress Requires Interaction with p21-Activated Protein Kinase Pak2/{gamma}-PAK

S. M. Shahjahan Miah,1 Kiyonao Sada,1* Polygena T. Tuazon,2 Jun Ling,2 Koichiro Maeno,1 Shinkou Kyo,1 Xiujuan Qu,1 Yumi Tohyama,1 Jolinda A. Traugh,2 and Hirohei Yamamura1*

Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan,1 Department of Biochemistry, University of California, Riverside, California 925212

Received 9 June 2003/ Returned for modification 29 July 2003/ Accepted 24 September 2003

The p21-activated serine/threonine protein kinase Pak2/{gamma}-PAK and the nonreceptor type of protein tyrosine kinase Syk are known to be activated when the cells are exposed to osmotic stress. The purpose of the present study was to examine whether Pak2 and Syk functionally cooperate in cellular signaling. Cotransfection studies revealed that Pak2 associates with Syk in COS cells. The constitutively active form of Cdc42 increases the association of Pak2 with Syk. Pak2 coexpressed with an inactive form of Cdc42 or kinase-inactive Pak2 interacts to a lesser extent with Syk, suggesting that Pak2-Syk association is enhanced by Pak2 activation. Interaction with Pak2 enhances the intrinsic kinase activity of Syk. This is supported by in vitro studies showing that Pak2 phosphorylates and activates Syk. Treatment of cells with sorbitol to induce hyperosmolarity results in the translocation of Pak2 and Syk to the region surrounding the nucleus and in dramatic enhancement of their association. Furthermore, cotransfection of Pak2 and Syk leads to the activation of c-Jun N-terminal kinase (JNK) under hyperosmotic conditions. Pak2 short interfering RNA suppresses sorbitol-mediated activation of endogenous Syk and JNK, thus identifying a novel pathway for JNK activation by Cdc42. These results demonstrate that Pak2 and Syk positively cooperate to regulate cellular responses to stress.

* Corresponding author. Mailing address: 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5400. Fax: 81-78-382-5418. E-mail for Kiyonao Sada: ksada{at}med.kobe-u.ac.jp. E-mail for Hirohei Yamamura: yamamura{at}kobe-u.ac.jp.

Molecular and Cellular Biology, January 2004, p. 71-83, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.71-83.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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