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J. Biol. Chem., Vol. 281, Issue 42, 31627-31637, October 20, 2006

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Phosphorylation and Up-regulation of Diacylglycerol Kinase via Its Interaction with Protein Kinase C^*

From the Biosignal Research Center, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan

Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. PKC directly associated with DGK through its accessory domain (AD), depending on Ca²⁺ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that PKC phosphorylated Ser-776 and Ser-779 in the AD of DGK. The phosphorylation by PKC resulted in activation of DGK because a DGK mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGK and an unphosphorylatable DGK mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGK by PKC could be confirmed in vivo, and overexpression of the AD of DGK inhibited re-translocation of PKC. These results demonstrate that localization and activation of the functionally correlated kinases, PKC and DGK, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGK and DAG signaling.

Received for publication, July 24, 2006

^* This work was supported by the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science, and Technology of Japan, grants from Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants-in-aid for scientific research on priority areas "Molecular Brain Science" and "Nuclear Dynamics" and by CREST, Japan Science and Technology Agency, and Takeda Science Foundation. 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.

¹ To whom correspondence should be addressed. Tel.: 81-78-803-5961; Fax: 81-78-803-5971; E-mail: naosaito{at}kobe-u.ac.jp.

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