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

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 (ECS(WSB-1)). In the developing tibial growth plate, Hedgehog-stimulated D2 ubiquitination via ECS(WSB-1) induces parathyroid hormone-related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECS(WSB-1) mediates a mechanism by which 'systemic' thyroid hormone can effect local control of the Hedgehog-PTHrP negative feedback loop and thus skeletogenesis.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Cell Differentiation, Chick Embryo, Chondrocytes, Gene Expression, Growth Plate, Hedgehog Proteins, Humans, Immunoprecipitation, In Situ Hybridization, Iodide Peroxidase, Mice, Models, Biological, Models, Molecular, Molecular Sequence Data, Mutation, Parathyroid Hormone-Related Protein, Protein Binding, Protein Subunits, Proteins, RNA Interference, Sequence Homology, Amino Acid, Thyroid Hormones, Tibia, Trans-Activators, Transcription Factors, Transfection, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases, beta-Transducin Repeat-Containing Proteins
Nat. Cell Biol.
Date: Jul. 01, 2005
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