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

Mol Endocrinol. 2001 Jun;15(6):936-45. doi: 10.1210/mend.15.6.0645.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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


  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Glycoproteins
  • Growth Inhibitors
  • Oligonucleotides, Antisense
  • Phosphoproteins
  • Receptors, Growth Factor
  • Receptors, Peptide
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad2 protein, rat
  • Smad5 Protein
  • Smad5 protein, mouse
  • Smad5 protein, rat
  • Testicular Hormones
  • Trans-Activators
  • anti-Mullerian hormone receptor
  • Anti-Mullerian Hormone
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I