The transforming growth factor β (TGF-β) superfamily contains over 35 cytokines including TGF-βs, bone morphogenic proteins (BMPs) and anti-Müllerian hormone (AMH). In cancer, TGF-β ligands act as a double-edged sword, performing tumor suppressor and metastatic enhancer functions, in a cell context dependent manner. In comparison to other members of the family, considerably less is known about the regulation of AMH signaling. Recently, AMH has been proposed as a therapeutic agent in ovarian cancer. In light of the pro-tumorigenic role proposed for BMP in ovarian cancer, such proposition implies a differential signaling output for AMH and BMP, as both ligands utilize the same type I receptors and Smads. We hypothesize that, as with TGF-β and BMP, AMH receptor oligomerization is a determinant of its signaling output and thus may have a role in the growth-inhibitory effect of AMH in ovarian cancer. Our findings show that AMHRII extensively homo- and hetero- oligomerizes at the plasma membrane prior to ligand binding. Moreover, a dissection of this interaction identified the contribution of the cytoplasmic domain of AMHRII, and the involvement of S-S bonds, to its homo-oligomerization. Additionally, FRAP analysis revealed that in unstimulated cells, ~ 60 % of AMHRII is immobile on the cell surface, suggesting its inclusion into macromolecular complexes. The extent and stability of AMHRII interactions is unique among type II receptors of the TGF-β superfamily, and in sharp contrast to those of the BMPRII. We hypothesize that such unique membrane organization may serve as a basis for differences in the cellular interpretation to AMH and BMP stimuli. Indeed, preliminary studies employing recombinant AMH and ES-2 ovarian cancer cells show marked differences in the balance of activation of canonical vs. non-canonical signaling between AMH and BMP2. The importance of these studies is underscored by the lack of effective treatment for ovarian cancer.
