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Protein Kinase CK2: A Window into the Posttranslational Regulation of the E(spl)/HES Repressors from Invertebrates and Vertebrates

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Protein Kinase CK2 Cellular Function in Normal and Disease States

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 12))

Abstract

The basic helix-loop-helix (bHLH) repressors encoded by the Drosophila Enhancer of split Complex (E(spl)C) are the terminal effectors of Notch signaling, a pathway that is highly conserved through Metazoa. Although the E(spl) proteins are structurally conserved, one region that exhibits length and sequence heterogeneity is the C-terminal domain (CtD), which links the b/HLH domains to the terminal WRPW tetrapeptide, facilitating recruitment of the corepressor Groucho. Consequently, the CtD has been largely thought to act as a nonfunctional linker. However, studies are revealing that this region is not only key to controlling E(spl) repressor activity (cis-inhibition) but is subject to sophisticated regulation through posttranslational modifications (PTM). These modifications are mediated by protein kinases, phosphatase(s), and accessory factors, which together regulate phospho-occupancy, conferring spatial and temporal control over E(spl) protein activities and levels. We suggest that E(spl)M8 is a paradigm for understanding the regulation of mammalian E(spl) homologues by PTM. In the case of E(spl)M8, repressor activity first requires multisite phosphorylation led by CK2, with steady state control provided by the phosphatase PP2A. The later participation of additional kinases would activate a phosphodegron, enabling timely clearance of the protein. Controlled activation and deactivation may both be essential for repeated rounds of Notch signaling, employing different E(spl) repressors. This mode of regulation likely impacts a preponderance of E(spl) members, underscoring its importance to Notch signaling. PTM therefore imposes greater functional diversity among the E(spl) proteins, which are themselves differentially expressed during development. Aberrant posttranslational modification of the human E(spl) homologues, the HES proteins, may underlie diverse developmental disorders and cancer, both of which have been linked to defects in Notch signaling.

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Acknowledgments

Supported by a grant from the National Institutes of Health (EY015718) to A. P. B.

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Authors and Affiliations

  1. Department of Biology, West Virginia University, Life Sciences Building, 53 Campus Drive, Morgantown, WV, 26506, USA

    Adam T. Majot, Tyler R. Sizemore, Mohna Bandyopadhyay, Lucas M. Jozwick & Ashok P. Bidwai

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  1. Adam T. Majot
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  2. Tyler R. Sizemore
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  3. Mohna Bandyopadhyay
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  4. Lucas M. Jozwick
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  5. Ashok P. Bidwai
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Correspondence to Ashok P. Bidwai .

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Editors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School and Minneapolis VA Health Care System, Minneapolis, Minnesota, USA

    Khalil Ahmed

  2. Dept of Biochemistry & Molecular Biology, University of Southern Denmark, Odense, Denmark

    Olaf-Georg Issinger

  3. Department of Molecular Biology, The John Paul II Catholic U. of Lublin Institute of Biotechnology, Lublin, Poland

    Ryszard Szyszka

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Majot, A.T., Sizemore, T.R., Bandyopadhyay, M., Jozwick, L.M., Bidwai, A.P. (2015). Protein Kinase CK2: A Window into the Posttranslational Regulation of the E(spl)/HES Repressors from Invertebrates and Vertebrates. In: Ahmed, K., Issinger, OG., Szyszka, R. (eds) Protein Kinase CK2 Cellular Function in Normal and Disease States. Advances in Biochemistry in Health and Disease, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-319-14544-0_6

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