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.
Dentice
Monica
M
Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Bandyopadhyay
Amitabha
A
Gereben
Balázs
B
Callebaut
Isabelle
I
Christoffolete
Marcelo A
MA
Kim
Brian W
BW
Nissim
Sahar
S
Mornon
Jean-Paul
JP
Zavacki
Ann Marie
AM
Zeöld
Anikó
A
Capelo
Luciane P
LP
Curcio-Morelli
Cyntia
C
Ribeiro
Rogério
R
Harney
John W
JW
Tabin
Clifford J
CJ
Bianco
Antonio C
AC
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D000075065:Elongin; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006132:Growth Plate / Q000196:embryology / Q000378:metabolism*; D053823:Hedgehog Proteins; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D013977:Tibia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics; D000097564:Iodothyronine Deiodinase Type II
D000075065:Elongin; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007453:Iodide Peroxidase; D044162:Parathyroid Hormone-Related Protein; D021122:Protein Subunits; D011506:Proteins; D013963:Thyroid Hormones; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins; D000097564:Iodothyronine Deiodinase Type II; C120287:WSB1 protein, human; C503398:Wsb1 protein, mouse