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

Monica Dentice, Amitabha Bandyopadhyay, Balázs Gereben, Isabelle Callebaut, Marcelo A. Christoffolete, Brian W. Kim, Sahar Nissim, Jean Paul Mornon, Ann Marie Zavacki, Anikó Zeöld, Luciane P. Capelo, Cyntia Curcio-Morelli, Rogério Ribeiro, John W. Harney, Clifford J. Tabin, Antonio C. Bianco

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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.

Original languageEnglish
Pages (from-to)698-705
Number of pages8
JournalNature Cell Biology
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 1 2005

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Dentice, M., Bandyopadhyay, A., Gereben, B., Callebaut, I., Christoffolete, M. A., Kim, B. W., Nissim, S., Mornon, J. P., Zavacki, A. M., Zeöld, A., Capelo, L. P., Curcio-Morelli, C., Ribeiro, R., Harney, J. W., Tabin, C. J., & Bianco, A. C. (2005). The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nature Cell Biology, 7(7), 698-705. https://doi.org/10.1038/ncb1272