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

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2001-06, Vol.15 (6), p.936-945
• Main Authors: Visser, J A, Olaso, R, Verhoef-Post, M, Kramer, P, Themmen, A P, Ingraham, H A
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I; Animals; Anti-Mullerian Hormone; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - metabolism; Cell Line; DNA-Binding Proteins - metabolism; Embryo, Mammalian - metabolism; Embryo, Mammalian - physiology; Female; Gene Expression Regulation - genetics; Genes, Reporter; Glycoproteins; Growth Inhibitors - metabolism; Male; Mice; Mullerian Ducts - embryology; Oligonucleotides, Antisense; Organ Culture Techniques; Phosphoproteins - metabolism; Protein-Serine-Threonine Kinases - metabolism; Rats; Receptors, Growth Factor - genetics; Receptors, Growth Factor - metabolism; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Receptors, Transforming Growth Factor beta; Recombinant Fusion Proteins - metabolism; Signal Transduction - physiology; Smad2 Protein; Smad5 Protein; Testicular Hormones - metabolism; Trans-Activators - metabolism; Transfection
• ISSN: 0888-8809
• DOI: 10.1210/me.15.6.936

Müllerian inhibiting substance (MIS or anti-Müllerian hormone) is a member of the transforming growth factor-beta family and plays a pivotal role in proper male sexual differentiation. Members of this family signal by the assembly 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 identity of the type I receptor is unclear. Here we report that MIS activates a bone 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 strategies showed that ALK2 is essential for MIS-induced signaling in two independent assays, the cellular Tlx-2 reporter gene assay and the Müllerian duct regression organ culture assay. In contrast, ALK6, the other candidate MIS type I receptor, was not required. Expression analyses revealed that ALK2 is present in all MIS target tissues including the mesenchyme surrounding the epithelial Müllerian duct. Collectively, we conclude that MIS employs a bone morphogenetic protein-like signaling pathway and uses ALK2 as its type I receptor. The use of this ubiquitously expressed type I receptor underscores the role of the MIS ligand and the MIS type II receptor in establishing the specificity of the MIS signaling cascade.