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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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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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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DOI: https://doi.org/10.1038/ncb1272
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