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Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase

Nature Cell Biology volume 11, pages 409–419 (2009)Cite this article

Abstract

Protein kinases have central functions in various cellular signal transduction pathways through their substrate phosphorylation. Here we show that a protein kinase, DYRK2, has unexpected role as a scaffold for an E3 ubiquitin ligase complex. DYRK2 associates with an E3 ligase complex containing EDD, DDB1 and VPRBP proteins (EDVP complex). Strikingly, DYRK2 serves as a scaffold for the EDVP complex, because small-interfering-RNA-mediated depletion of DYRK2 disrupts the formation of the EDD–DDB1–VPRBP complex. Although the kinase activity of DYRK2 is dispensable for its ability to mediate EDVP complex formation, it is required for the phosphorylation and subsequent degradation of its downstream substrate, katanin p60. Collectively, our results reveal a new type of E3-ubiquitin ligase complex in humans that depends on a protein kinase for complex formation as well as for the subsequent phosphorylation, ubiquitylation and degradation of their substrates.

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Figure 1: Identification of EDD–DDB1–VPRBP as DYRK2-associated proteins.
Figure 2: DYRK2 functions as an adaptor in the EDVP E3 ligase complex.
Figure 3: Katanin p60 is the ubiquitylation substrate for EDVP E3 ligase complex.
Figure 4: EDVP E3 ligase complex regulates katanin p60 protein levels.
Figure 5: DYRK2 phosphorylates katanin.
Figure 6: DYRK2 kinase activity is required for the regulation of katanin degradation.
Figure 7: DYRK2 regulates mitotic progression by means of its adaptor and kinase function.

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Acknowledgements

We thank Jamie Wood for critical reading of the manuscript and for providing valuable suggestions. We thank Amanda Russell for providing EDD expression vectors. This work was supported in part by grants from the National Institutes of Health (to J.C.). J.C. is a recipient of an Era of Hope Scholars award from the Department of Defense and is a member of Mayo Clinic Breast SPORE programme.

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  1. Department of Therapeutic Radiology, Yale University School of Medicine, PO Box 208040, New Haven, 06520, Connecticut, USA

    Subbareddy Maddika & Junjie Chen

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  1. Subbareddy Maddika
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  2. Junjie Chen
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S.M. performed all the experiments. S.M. and J.C. designed the experiments, analysed the data and wrote the manuscript.

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Correspondence to Junjie Chen.

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Maddika, S., Chen, J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol 11, 409–419 (2009). https://doi.org/10.1038/ncb1848

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