Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II.

The levels and intracellular localization of wild type Transforming Growth Factor β superfamily (TGFβ-SF) receptors are tightly regulated by endocytic trafficking, shedding and degradation. In contrast, a main regulatory mechanism of mutation-bearing receptors involves their intracellular retention. Anti-Mullerian hormone receptor II (AMHRII) is the type-II receptor for anti-Mullerian hormone (AMH), a TGFβ-SF ligand that mediates Mullerian duct regression in males. Here, we studied AMHRII processing and identified novel mechanisms of its constitutive negative regulation. Immunoblot analysis revealed that a significant portion of AMHRII was missing most of its extra-cellular domain (ECD), and although glycosylated, was unfolded and retained in the endoplasmic reticulum. Exogenous expression of AMHRII, but not of type-II TGF-β receptor (TβRII), resulted in its disulfide-bond-mediated homo-oligomerization and intracellular retention, and in a decrease in its AMH binding capacity. At the plasma-membrane AMHRII differed from TβRII, forming high levels of non-covalent homomeric complexes, which exhibited a clustered distribution and restricted lateral mobility. This study identifies novel mechanisms of negative regulation of a type-II TGFβ-SF receptor through cleavage, intracellular retention and/or promiscuous disulfide-bond mediated homo-oligomerization.