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Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.

Abstract : 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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122137
Contributor : Laurent Jonchère <>
Submitted on : Tuesday, March 3, 2015 - 1:16:03 PM
Last modification on : Wednesday, September 16, 2020 - 4:57:23 PM

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Nathalie Di Clemente, Soazik P Jamin, Alexey Lugovskoy, Paul Carmillo, Christian Ehrenfels, et al.. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.. Molecular Endocrinology -Baltimore-, Endocrine Society, 2010, 24 (11), pp.2193-206. ⟨10.1210/me.2010-0273⟩. ⟨hal-01122137⟩

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