Letter abstract
Nature Cell Biology 7, 698 - 705 (2005)
Published online: 19 June 2005 | doi:10.1038/ncb1272
The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate
Monica Dentice1, Amitabha Bandyopadhyay2, Balázs Gereben3, Isabelle Callebaut4, Marcelo A. Christoffolete1, Brian W. Kim1, Sahar Nissim2, Jean-Paul Mornon4, Ann Marie Zavacki1, Anikó Zeöld3, Luciane P. Capelo1, Cyntia Curcio-Morelli1, Rogério Ribeiro1, John W. Harney1, Clifford J. Tabin2 & Antonio C. Bianco1
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.
- Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary.
- Département de Biologie Structurale, LMCP, CNRS UMR7590, Universities Paris 6 and Paris 7, Paris 75252 Cedex 05, France.
Correspondence to: Antonio C. Bianco1 e-mail: abianco@partners.org
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