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PMID:11376112

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Citation

Visser, JA, Olaso, R, Verhoef-Post, M, Kramer, P, Themmen, AP and Ingraham, HA (2001) The serine/threonine transmembrane receptor ALK2 mediates Müllerian inhibiting substance signaling. Mol. Endocrinol. 15:936-45

Abstract

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.

Links

PubMed

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:BMR1B

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMR1B

enables

GO:0005025: transforming growth factor beta receptor activity, type I

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ACVR1

located_in

GO:0005887: integral component of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MIS

enables

GO:0005160: transforming growth factor beta receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MIS

acts_upstream_of_or_within

GO:0001655: urogenital system development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MIS

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ACVR1

acts_upstream_of_or_within

GO:0001655: urogenital system development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AMHR2

located_in

GO:0005887: integral component of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:AMHR2

acts_upstream_of_or_within

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AMHR2

enables

GO:0005026: transforming growth factor beta receptor activity, type II

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SMAD5

acts_upstream_of_or_within

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACVR1

part_of

GO:0005887: integral component of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACVR1

acts_upstream_of_or_within

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACVR1

enables

GO:0016361: activin receptor activity, type I

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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