Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS), is a member of the Transforming growth factor Beta (TGFB) superfamily (Massagué 1998). It plays a crucial role during male sexual differentiation, inducing the regression of the Müllerian ducts in male fetuses (Nef & Parada 2000). Mutations in the AMH gene (Cate et al.1986) cause Persistent Müllerian duct syndrome, a rare form of male pseudohermaphroditism (Belville et al. 1999, MacLaughlin & Donahoe 2004). As a member of the TGFB superfamily, it was expected that AMH signaling would resemble the signaling pathways defined for other family members (Visser 2003). TGFB family members signal through a heteromeric receptor complex consisting of two related serine/threonine kinase receptors, the type I and II receptors. The dimeric ligand initially binds to the type II receptor, which recruits and phosphorylates the type I receptor. This activates the type I receptor resulting in phosphorylation of Smad proteins.
Prior to secretion, AMH undergoes glycosylation and dimerization to produce a 144-kDa dimer composed of identical disulphide-linked 72-kDa monomer subunits; each monomer contains an N-terminal domain 'pro' region and a C-terminal domain 'mature' region. The type II receptor for AMH is AMHR2 (Baarends et al. 1994, di Clemente et al. 1994, Teixeira et al. 1996). AMH must be cleaved to bind AMHR2 but dissociation of the pro-region from the mature C-terminal dimer is not required for this initial interaction (di Clemente et al. 2010). The AMH:AMHR2 complex has been reported to recruit in a context specific manner two candidate type I receptors, Bone morphogenetic protein receptor type-1B (BMPR1A, ALK3) (Jamin et al. 2002), and Activin receptor type-1 (ACVR1, ALK2) (Clarke et al. 2001, Visser et al. 2001) leading to SMAD1/5/8 activation (Gouedard et al. 2000, Zhan et al. 2006).