The serine/threonine transmembrane receptor ALK2 mediates Müllerian inhibiting substance signaling.
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.
Visser
J A
JA
Department of Physiology, University of California San Francisco, 513 Parnassus, San Francisco, CA 94143-0444, USA.
Olaso
R
R
Verhoef-Post
M
M
Kramer
P
P
Themmen
A P
AP
Ingraham
H A
HA
D030201:Activin Receptors, Type I; D000818:Animals; D054304:Anti-Mullerian Hormone; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009095:Mullerian Ducts / Q000196:embryology; D016376:Oligonucleotides, Antisense; D009924:Organ Culture Techniques; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051902:Smad5 Protein; D013735:Testicular Hormones / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006131:Growth Inhibitors; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D017978:Receptors, Growth Factor; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C497784:Smad2 protein, rat; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; C497799:Smad5 protein, rat; D013735:Testicular Hormones; D015534:Trans-Activators; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I