Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.
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.
di Clemente
Nathalie
N
Institut National de la Santé et de la Recherche Médicale U782, 32 rue des Carnets, Clamart F-92140, France.
Jamin
Soazik P
SP
Lugovskoy
Alexey
A
Carmillo
Paul
P
Ehrenfels
Christian
C
Picard
Jean-Yves
JY
Whitty
Adrian
A
Josso
Nathalie
N
Pepinsky
R Blake
RB
Cate
Richard L
RL
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000737:chemistry / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011961:Receptors, Fc / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D011961:Receptors, Fc; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone