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

被引:132
作者
Visser, JA
Olaso, R
Verhoef-Post, M
Kramer, P
Themmen, APN
Ingraham, HA
机构
[1] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Grad Program Biomed Sci, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Grad Program Dev Biol, San Francisco, CA 94143 USA
[4] Erasmus Univ, Dept Endocrinol & Reprod, NL-3000 DR Rotterdam, Netherlands
关键词
D O I
10.1210/me.15.6.936
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Mullerian inhibiting substance (MIS or anti-Mullerian 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 Mullerian 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 Mullerian 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.
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页码:936 / 945
页数:10
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