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J. Biol. Chem., Vol. 280, Issue 5, 3323-3330, February 4, 2005

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Activation of p21-activated Kinase 6 by MAP Kinase Kinase 6 and p38 MAP Kinase^*

Ramneet Kaur, Xia Liu¶, Ole Gjoerup||, Aihua Zhang¶, Xin Yuan, Steven P. Balk, Michael C. Schneider¶, and Michael L. Lu¶**

From the Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, the ^¶Urology Research Laboratory, Department of Surgery, Brigham and Women's Hospital, and the ^||Department of Cancer Biology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115

The p21-activated kinases (PAKs) contain an N-terminal Cdc42/Rac interactive binding domain, which in the group 1 PAKs (PAK1, 2, and 3) regulates the activity of an adjacent conserved autoinhibitory domain. In contrast, the group 2 PAKs (PAK4, 5, and 6) lack this autoinhibitory domain and are not activated by Cdc42/Rac binding, and the mechanisms that regulate their kinase activity have been unclear. This study found that basal PAK6 kinase activity was repressed by a p38 mitogen-activated protein (MAP) kinase antagonist and could be strongly stimulated by constitutively active MAP kinase kinase 6 (MKK6), an upstream activator of p38 MAP kinases. Mutation of a consensus p38 MAP kinase target site at serine 165 decreased PAK6 kinase activity. Moreover, PAK6 was directly activated by MKK6, and mutation of tyrosine 566 in a consensus MKK6 site (threonine-proline-tyrosine, TPY) in the activation loop of the PAK6 kinase domain prevented activation by MKK6. PAK6 activation by MKK6 was also blocked by mutation of an autophosphorylated serine (serine 560) in the PAK6 activation loop, indicating that phosphorylation of this site is necessary for MKK6-mediated activation. PAK4 and PAK5 were similarly activated by MKK6, consistent with a conserved TPY motif in their activation domains. The activation of PAK6 by both p38 MAP kinase and MKK6 suggests that PAK6 plays a role in the cellular response to stress-related signals.

Received for publication, June 16, 2004 , and in revised form, November 9, 2004.

^* This work was supported by National Cancer Institute Grant CA8799701 and Department of Defense Grant DAMD17-02-1-0017. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: LMRC-BLI-143, Urology Research Laboratory, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115. Tel.: 617-732-6430; E-mail: mlu{at}rics.bwh.harvard.edu.

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