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J. Cell Biol. 160 (6): 929-937

Copyright © 2003 by the Rockefeller University Press.

Article

Association of diacylglycerol kinase {zeta} with protein kinase C {alpha}

spatial regulation of diacylglycerol signaling

Bai Luo1,2, Stephen M. Prescott1,2,3, and Matthew K. Topham1,3

1 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
2 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
3 Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112

Address correspondence to Matthew K. Topham, The Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112. Tel.: (801) 585-0304. Fax: (801) 585-6345. E-mail: matt.topham{at}hci.utah.edu

Abstract: Activation of PKC depends on the availability of DAG, a signaling lipid that is tightly and dynamically regulated. DAG kinase (DGK) terminates DAG signaling by converting it to phosphatidic acid. Here, we demonstrate that DGK{zeta} inhibits PKC{alpha} activity and that DGK activity is required for this inhibition. We also show that DGK{zeta} directly interacts with PKC{alpha} in a signaling complex and that the binding site in DGK{zeta} is located within the catalytic domain. Because PKC{alpha} can phosphorylate the myristoylated alanine-rich C-kinase substrate (MARCKS) motif of DGK{zeta}, we tested whether this modification could affect their interaction. Phosphorylation of this motif significantly attenuated coimmunoprecipitation of DGK{zeta} and PKC{alpha} and abolished their colocalization in cells, indicating that it negatively regulates binding. Expression of a phosphorylation-mimicking DGK{zeta} mutant that was unable to bind PKC{alpha} did not inhibit PKC{alpha} activity. Together, our results suggest that DGK{zeta} spatially regulates PKC{alpha} activity by attenuating local accumulation of signaling DAG. This regulation is impaired by PKC{alpha}-mediated DGK{zeta} phosphorylation.

Key Words: diacylglycerol; diacylglycerol kinase; protein kinase C; spatial regulation; phosphorylation

* Abbreviations used in this paper: DGK, DAG kinase; MARCKS, myristoylated alanine-rich C-kinase substrate; PA, phosphatidic acid; PSD, phosphorylation site domain; RasGRP, Ras guanyl nucleotide–releasing protein.

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