The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling

Mullerian inhibiting substance (MIS or anti-Mullerian hormone) is a member of the transforming growth factor-beta family and plays a pivotal role in p roper male sexual differentiation. Members of this family signal by the ass embly of two related serine/threonine kinase receptors, referred to as type I or type II receptors, and downstream cytoplasmic Smad effector proteins. Although the MIS type II receptor (MISRII) has been identified, the identi ty of the type I receptor is unclear. Here we report that MIS activates a b one morphogenetic protein-like signaling pathway, which is solely dependent on the presence of the MISRII and bioactive MIS ligand. Among the multiple type I candidates tested, only ALK2 resulted in significant enhancement of the MIS signaling response. Furthermore, dominant-negative and antisense s trategies showed that ALK2 is essential for MIS-induced signaling in two in dependent assays, the cellular Tlx-2 reporter gene assay and the Mullerian duct regression organ culture assay. In contrast, ALK6, the other candidate MIS type I receptor, was not required. Expression analyses revealed that A LK2 is present in all MIS target tissues including the mesenchyme surroundi ng the epithelial Mullerian duct. Collectively, we conclude that MIS employ s a bone morphogenetic protein-like signaling pathway and uses ALK2 as its type I receptor. The use of this ubiquitously expressed type I receptor und erscores the role of the MIS ligand and the MIS type II receptor in establi shing the specificity of the MIS signaling cascade.