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 (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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites / genetics
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Chick Embryo
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Chondrocytes / drug effects
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Chondrocytes / metabolism
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Elongin
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Gene Expression / drug effects
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Gene Expression / genetics
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Growth Plate / embryology
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Growth Plate / metabolism*
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Hedgehog Proteins
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Humans
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Immunoprecipitation
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In Situ Hybridization
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Intracellular Signaling Peptides and Proteins
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Iodide Peroxidase / genetics
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Iodide Peroxidase / metabolism
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Iodothyronine Deiodinase Type II
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Mice
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Models, Biological
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Parathyroid Hormone-Related Protein / metabolism*
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Protein Binding
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Protein Subunits / physiology
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Proteins / genetics
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Proteins / metabolism
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Proteins / physiology*
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RNA Interference
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Sequence Homology, Amino Acid
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Thyroid Hormones / metabolism*
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Thyroid Hormones / pharmacology
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Tibia / cytology
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Tibia / drug effects
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Tibia / metabolism
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Trans-Activators / genetics
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Trans-Activators / pharmacology
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Trans-Activators / physiology*
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Transcription Factors / metabolism
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Transfection
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Two-Hybrid System Techniques
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitin-Protein Ligases / physiology*
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beta-Transducin Repeat-Containing Proteins / genetics
Substances
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Elongin
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Hedgehog Proteins
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Intracellular Signaling Peptides and Proteins
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Parathyroid Hormone-Related Protein
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Protein Subunits
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Proteins
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Thyroid Hormones
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Trans-Activators
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Transcription Factors
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Ubiquitin
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WSB1 protein, human
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Wsb1 protein, mouse
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beta-Transducin Repeat-Containing Proteins
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Iodide Peroxidase
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Ubiquitin-Protein Ligases