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The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate

Nature Cell Biology volume 7, pages 698–705 (2005)Cite this article

Abstract

WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by Hedgehog signalling in embryonic structures during chicken development. Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop in D2 that confers metabolic instability, whereas the SOCS-box domain mediates its interaction with a ubiquitinating catalytic core complex, modelled as Elongin BC–Cul5–Rbx1 (ECSWSB-1). In the developing tibial growth plate, Hedgehog-stimulated D2 ubiquitination via ECSWSB-1 induces parathyroid hormone-related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECSWSB-1 mediates a mechanism by which 'systemic' thyroid hormone can effect local control of the Hedgehog–PTHrP negative feedback loop and thus skeletogenesis.

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Figure 1: WSB-1 is a component of a D2-specific E3 ubiquitin ligase.
Figure 2: WSB-1 is the primary substrate recognition factor for D2.
Figure 3: Composition of the ECSWSB-1 catalytic core complex.
Figure 4: D2 contains an 18-amino-acid destruction loop.
Figure 5: Hedgehog signalling decreases D2 by inducing WSB-1.

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Acknowledgements

We thank P. R. Larsen, H. Kronenberg and D. Salvatore for helpful insights and comments on the manuscript. This work was supported by DK058538, DK56246 and TW006467 NIH grants.

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Authors and Affiliations

  1. Division of Endocrinology, Thyroid Section, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA

    Monica Dentice, Marcelo A. Christoffolete, Brian W. Kim, Ann Marie Zavacki, Luciane P. Capelo, Cyntia Curcio-Morelli, Rogério Ribeiro, John W. Harney & Antonio C. Bianco

  2. Department of Genetics, Harvard Medical School, Boston, 02115, MA, USA

    Amitabha Bandyopadhyay, Sahar Nissim & Clifford J. Tabin

  3. Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083, Hungary

    Balázs Gereben & Anikó Zeöld

  4. Département de Biologie Structurale, LMCP, CNRS UMR7590, Universities Paris 6 and Paris 7, Paris, 75252, Cedex 05, France

    Isabelle Callebaut & Jean-Paul Mornon

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Correspondence to Antonio C. Bianco.

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Dentice, M., Bandyopadhyay, A., Gereben, B. et al. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 7, 698–705 (2005). https://doi.org/10.1038/ncb1272

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