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Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.
di Clemente, Nathalie; Jamin, Soazik P; Lugovskoy, Alexey; Carmillo, Paul; Ehrenfels, Christian; Picard, Jean-Yves; Whitty, Adrian; Josso, Nathalie; Pepinsky, R Blake; Cate, Richard L.
Afiliación
  • di Clemente N; Institut National de la Santé et de la Recherche Médicale U782, 32 rue des Carnets, Clamart F-92140, France.
Mol Endocrinol ; 24(11): 2193-206, 2010 Nov.
Article en En | MEDLINE | ID: mdl-20861221
TGF-ß 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-ß 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-ß 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Procesamiento Proteico-Postraduccional / Factor de Crecimiento Transformador beta / Receptores de Factores de Crecimiento Transformadores beta / Receptores de Péptidos / Proteínas Smad / Hormona Antimülleriana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Endocrinol Asunto de la revista: BIOLOGIA MOLECULAR / ENDOCRINOLOGIA Año: 2010 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Procesamiento Proteico-Postraduccional / Factor de Crecimiento Transformador beta / Receptores de Factores de Crecimiento Transformadores beta / Receptores de Péptidos / Proteínas Smad / Hormona Antimülleriana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Endocrinol Asunto de la revista: BIOLOGIA MOLECULAR / ENDOCRINOLOGIA Año: 2010 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos