Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta
| Autor: | Christian W. Ehrenfels, Nathalie Josso, Jean-Yves Picard, Paul Carmillo, Soazik P. Jamin, Nathalie di Clemente, R. Blake Pepinsky, Adrian Whitty, Alexey Lugovskoy, Richard L. Cate |
|---|---|
| Přispěvatelé: | Endocrinologie et Génétique de la Reproduction et du Développement, Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Anti-Mullerian Hormone
Receptor complex Receptors Peptide Dimer [SDV]Life Sciences [q-bio] Smad Proteins Receptors Fc Biology Models Biological Serine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Transforming Growth Factor beta Chlorocebus aethiops Animals Humans Phosphorylation Receptor Molecular Biology Original Research 030304 developmental biology 0303 health sciences 030219 obstetrics & reproductive medicine COS cells Ligand General Medicine Transforming growth factor beta Cell biology Solubility Biochemistry chemistry COS Cells biology.protein Protein Multimerization Protein Processing Post-Translational Receptors Transforming Growth Factor beta |
| Zdroj: | Molecular Endocrinology-Baltimore Molecular Endocrinology-Baltimore-, Endocrine Society, 2010, 24 (11), pp.2193-206. ⟨10.1210/me.2010-0273⟩ |
| ISSN: | 0888-8809 |
| DOI: | 10.1210/me.2010-0273⟩ |
| Popis: | TGF-β family ligands are translated as prepropeptide precursors and are processed into mature C-terminal dimers that signal by assembling a serine/threonine kinase receptor complex containing type I and II components. Many TGF-β ligands are secreted in a latent form that cannot bind their receptor, due to the pro-region remaining associated with the mature ligand in a noncovalent complex after proteolytic cleavage. Here we show that anti-Müllerian hormone (AMH), a TGF-β family ligand involved in reproductive development, must be cleaved to bind its type II receptor (AMHRII), but dissociation of the pro-region from the mature C-terminal dimer is not required for this initial interaction. We provide direct evidence for this interaction by showing that the noncovalent complex binds to a soluble form of AMHRII in an ELISA format and to AMHRII immobilized on Sepharose. Binding of the noncovalent complex to Sepharose-coupled AMHRII induces dissociation of the pro-region from the mature C-terminal dimer, whereas no dissociation occurs after binding to immobilized AMH antibodies. The pro-region cannot be detected after binding of the AMH noncovalent complex to AMHRII expressed on COS cells, indicating that pro-region dissociation may occur as a natural consequence of receptor engagement on cells. Moreover, the mature C-terminal dimer is more active than the noncovalent complex in stimulating Sma- and Mad-related protein activation, suggesting that pro-region dissociation contributes to the assembly of the active receptor complex. AMH thus exemplifies a new mechanism for receptor engagement in which interaction with the type II receptor promotes pro-region dissociation to generate mature ligand. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|