Activation of Syk protein tyrosine kinase in response to osmotic stress requires interaction with p21-activated protein kinase Pak2/gamma-PAK.
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.
Miah
S M Shahjahan
SM
Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Sada
Kiyonao
K
Tuazon
Polygena T
PT
Ling
Jun
J
Maeno
Koichiro
K
Kyo
Shinkou
S
Qu
Xiujuan
X
Tohyama
Yumi
Y
Traugh
Jolinda A
JA
Yamamura
Hirohei
H
D000818:Animals; D019556:COS Cells; D004792:Enzyme Precursors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009997:Osmotic Pressure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D000072377:Syk Kinase; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D013012:Sorbitol; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein