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Protein kinase C regulates the nuclear localization of diacylglycerol kinase-ζ

Nature volume 394, pages 697–700 (1998)Cite this article

Abstract

Diacylglycerol kinases (DGKs) terminate signalling from diacylglycerol by converting it to phosphatidic acid1,2,3,4,5,6,7,8. Diacylglycerol regulates cell growth and differentiation, and its transient accumulation in the nucleus may be particularly important in this regulation9,10. Here we show that a fraction of DGK-ζ is found inthe nucleus, where it regulates the amount of nuclear diacylglycerol. Reducing nuclear diacylglycerol levels by conditional expression of DGK-ζ attenuates cell growth. The nuclear-localization signal of DGK-ζ is located in a region that is homologous to the phosphorylation-site domain of the MARCKS protein. This is, to our knowledge, the first evidence that this domain, which is amajor target for protein kinase C, can localize a protein to thenucleus. Two isoforms of protein kinase C, but not others, regulate the localization of DGK-ζ. Our results define a cycle in which diacylglycerol activates protein kinase C, which then regulates the metabolism of diacylglycerol by alternating the intracellular location of DGK-ζ. This may be a general mechanism to control mitogenic signals that depend on nuclear diacylglycerol.

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Figure 1: DGK-ζ is a nuclear protein and its MARCKS PSD is necessary and sufficient for nuclear targeting.
Figure 2: PKC controls nuclear localization of DGK-ζ, and overexpression of DGK-ζ regulates nuclear DAG and the cell cycle.
Figure 3: Introduction of negative charge into the MARCKS PSD excludes it from the nucleus.
Figure 4: Phosphorylation by PKC-α causes nuclear exclusion of DGK-ζ.

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Acknowledgements

We thank E. Kennington, M. Flynn, J. White and H. Rust for technical assistance, M.McAdams for peptide synthesis, and V. Bennett and A. Thorburn for discussions. This work was supported by a grant from the National Cancer Institute. The core facilities at the University of Utah (DNA Sequencing and Peptide/DNA User Facility) were supported by grants from the National Cancer Institute. P.J.B. was an Investigator of the Howard Hughes Medical Institute when this work was performed, and M.K.T. is a Howard Hughes Medical Institute Physician Postdoctoral Fellow.

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Authors and Affiliations

  1. The Huntsman Cancer Institute, Salt Lake City, 84112, Utah, USA

    Matthew K. Topham, Michaeline Bunting & Stephen M. Prescott

  2. Eccles Program in Human Molecular Biology & Genetics, Salt Lake City, 84112, Utah, USA

    Matthew K. Topham, Michaeline Bunting & Stephen M. Prescott

  3. Department of Internal Medicine, University of Utah, Salt Lake City, 84112, Utah, USA

    Matthew K. Topham, Michaeline Bunting, Guy A. Zimmerman, Thomas M. McIntyre & Stephen M. Prescott

  4. National Institute of Environmental Health Sciences, Research Triangle Park, 27709, North Carolina, USA

    Perry J. Blackshear

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Correspondence to Stephen M. Prescott.

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Topham, M., Bunting, M., Zimmerman, G. et al. Protein kinase C regulates the nuclear localization of diacylglycerol kinase-ζ. Nature 394, 697–700 (1998). https://doi.org/10.1038/29337

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