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J. Biol. Chem., Vol. 279, Issue 46, 47720-47725, November 12, 2004

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Protein Kinase C II Regulates Akt Phosphorylation on Ser-473 in a Cell Type- and Stimulus-specific Fashion^*

Yuko Kawakami, Hajime Nishimoto, Jiro Kitaura, Mari Maeda-Yamamoto, Roberta M. Kato¶, Dan R. Littman||, David J. Rawlings¶, and Toshiaki Kawakami**

From the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, the National Institute of Vegetables, and Tea Science, NARO, 2769 Kanaya, Shizuoka 428-8501, Japan, the ^¶Departments of Immunology and Pediatrics, University of Washington, School of Medicine, Seattle, Washington 98195, and the ^||Departments of Pathology and Microbiology, New York University, School of Medicine, Howard Hughes Medical Institute, New York, New York 10016

Akt (= protein kinase B), a subfamily of the AGC serine/threonine kinases, plays critical roles in survival, proliferation, glucose metabolism, and other cellular functions. Akt activation requires the recruitment of the enzyme to the plasma membrane by interacting with membrane-bound lipid products of phosphatidylinositol 3-kinase. Membrane-bound Akt is then phosphorylated at two sites for its full activation; Thr-308 in the activation loop of the kinase domain is phosphorylated by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser-473 in the C-terminal hydrophobic motif by a putative kinase PDK2. The identity of PDK2 has been elusive. Here we present evidence that conventional isoforms of protein kinase C (PKC), particularly PKCII, can regulate Akt activity by directly phosphorylating Ser-473 in vitro and in IgE/antigen-stimulated mast cells. By contrast, PKC is not required for Ser-473 phosphorylation in mast cells stimulated with stem cell factor or interleukin-3, in serum-stimulated fibroblasts, or in antigen receptor-stimulated T or B lymphocytes. Therefore, PKCII appears to work as a cell type- and stimulus-specific PDK2.

Received for publication, August 2, 2004 , and in revised form, September 8, 2004.

^* This work was supported by National Institutes of Health Grants AI38348 and AI33617 (to T. K.). This is Publication 577 from the La Jolla Institute for Allergy and Immunology. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Figs. S1–S4.

This article was selected as a Paper of the Week.

^** To whom correspondence should be addressed: La Jolla Inst. for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel.: 858-558-3538; Fax: 858-558-3526; E-mail: toshi{at}liai.org.

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