This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Visser, J. A. Articles by Ingraham, H. A. Search for Related Content PubMed PubMed Citation Articles by Visser, J. A. Articles by Ingraham, H. A.

The Serine/Threonine Transmembrane Receptor ALK2 Mediates Müllerian Inhibiting Substance Signaling

Department of Physiology (J.A.V., R.O., H.A.I.) Graduate Programs in Biomedical Sciences (H.A.I.) and Developmental Biology (H.A.I.) University of California, San Francisco San Francisco, California 94143-0444
Department of Endocrinology and Reproduction (M.V.P., P.K., A.P.N.T.) Erasmus University Rotterdam, The Netherlands

Müllerian inhibiting substance (MIS or anti-Müllerian hormone) is a member of the transforming growth factor-ß 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.

This article has been cited by other articles:

				C. Belville, J.-D. Marechal, S. Pennetier, P. Carmillo, L. Masgrau, L. Messika-Zeitoun, J. Galey, G. Machado, D. Treton, J. Gonzales, et al. Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport Hum. Mol. Genet., August 15, 2009; 18(16): 3002 - 3013. [Abstract] [Full Text] [PDF]

				K. A. Smith, I. C. Joziasse, S. Chocron, M. van Dinther, V. Guryev, M. C. Verhoeven, H. Rehmann, J. J. van der Smagt, P. A. Doevendans, E. Cuppen, et al. Dominant-Negative ALK2 Allele Associates With Congenital Heart Defects Circulation, June 23, 2009; 119(24): 3062 - 3069. [Abstract] [Full Text] [PDF]

				P. J. Malloy, L. Peng, J. Wang, and D. Feldman Interaction of the Vitamin D Receptor with a Vitamin D Response Element in the Mullerian-Inhibiting Substance (MIS) Promoter: Regulation of MIS Expression by Calcitriol in Prostate Cancer Cells Endocrinology, April 1, 2009; 150(4): 1580 - 1587. [Abstract] [Full Text] [PDF]

				X. Wu, S. Wan, S. Pujar, M. E. Haskins, D. H. Schlafer, M. M. Lee, and V. N. Meyers-Wallen A Single Base Pair Mutation Encoding a Premature Stop Codon in the MIS Type II Receptor Is Responsible for Canine Persistent Mullerian Duct Syndrome J Androl, January 1, 2009; 30(1): 46 - 56. [Abstract] [Full Text] [PDF]

				G.D. Orvis, S.P. Jamin, K.M. Kwan, Y. Mishina, V.M. Kaartinen, S. Huang, A.B. Roberts, L. Umans, D. Huylebroeck, A. Zwijsen, et al. Functional Redundancy of TGF-beta Family Type I Receptors and Receptor-Smads in Mediating Anti-Mullerian Hormone-Induced Mullerian Duct Regression in the Mouse Biol Reprod, June 1, 2008; 78(6): 994 - 1001. [Abstract] [Full Text] [PDF]

				M. E. Kevenaar, J. S. E. Laven, S. L. Fong, A. G. Uitterlinden, F. H. de Jong, A. P. N. Themmen, and J. A. Visser A Functional Anti-Mullerian Hormone Gene Polymorphism Is Associated with Follicle Number and Androgen Levels in Polycystic Ovary Syndrome Patients J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1310 - 1316. [Abstract] [Full Text] [PDF]

				N. Renlund, R. Pieretti-Vanmarcke, F. H. O'Neill, L. Zhang, P. K. Donahoe, and J. Teixeira c-Jun N-terminal Kinase Inhibitor II (SP600125) Activates Mullerian Inhibiting Substance Type II Receptor-Mediated Signal Transduction Endocrinology, January 1, 2008; 149(1): 108 - 115. [Abstract] [Full Text] [PDF]

				N. Renlund, F. H O'Neill, L. Zhang, Y. Sidis, and J. Teixeira Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor J. Endocrinol., October 1, 2007; 195(1): 95 - 103. [Abstract] [Full Text] [PDF]

				R. Pieretti-Vanmarcke, P. K. Donahoe, L. A. Pearsall, D. M. Dinulescu, D. C. Connolly, E. F. Halpern, M. V. Seiden, and D. T. MacLaughlin Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer PNAS, November 14, 2006; 103(46): 17426 - 17431. [Abstract] [Full Text] [PDF]

				T. T. Tran, D. L. Segev, V. Gupta, H. Kawakubo, G. Yeo, P. K. Donahoe, and S. Maheswaran Mullerian Inhibiting Substance Regulates Androgen-Induced Gene Expression and Growth in Prostate Cancer Cells through a Nuclear Factor-{kappa}B-Dependent Smad-Independent Mechanism Mol. Endocrinol., October 1, 2006; 20(10): 2382 - 2391. [Abstract] [Full Text] [PDF]

				S. Mazerbourg and A. J.W. Hsueh Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands Hum. Reprod. Update, July 1, 2006; 12(4): 373 - 383. [Abstract] [Full Text] [PDF]

				Y. Zhan, A. Fujino, D. T. MacLaughlin, T. F. Manganaro, P. P. Szotek, N. A. Arango, J. Teixeira, and P. K. Donahoe Mullerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells early in Mullerian duct regression Development, June 15, 2006; 133(12): 2359 - 2369. [Abstract] [Full Text] [PDF]

				R. Pieretti-Vanmarcke, P. K. Donahoe, P. Szotek, T. Manganaro, M. K. Lorenzen, J. Lorenzen, D. C. Connolly, E. F. Halpern, and D. T. MacLaughlin Recombinant Human Mullerian Inhibiting Substance Inhibits Long-term Growth of MIS Type II Receptor-Directed Transgenic Mouse Ovarian Cancers In vivo Clin. Cancer Res., March 1, 2006; 12(5): 1593 - 1598. [Abstract] [Full Text] [PDF]

				P.-Y. Wang, K. Koishi, A. B. McGeachie, M. Kimber, D. T. MacLaughlin, P. K. Donahoe, and I. S. McLennan Mullerian Inhibiting Substance acts as a motor neuron survival factor in vitro PNAS, November 8, 2005; 102(45): 16421 - 16425. [Abstract] [Full Text] [PDF]

				L. Vallier, M. Alexander, and R. A. Pedersen Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells J. Cell Sci., October 1, 2005; 118(19): 4495 - 4509. [Abstract] [Full Text] [PDF]

				S. Mazerbourg, K. Sangkuhl, C.-W. Luo, S. Sudo, C. Klein, and A. J. W. Hsueh Identification of Receptors and Signaling Pathways for Orphan Bone Morphogenetic Protein/Growth Differentiation Factor Ligands Based on Genomic Analyses J. Biol. Chem., September 16, 2005; 280(37): 32122 - 32132. [Abstract] [Full Text] [PDF]

				N. Josso, C. Belville, N. di Clemente, and J.-Y. Picard AMH and AMH receptor defects in persistent Mullerian duct syndrome Hum. Reprod. Update, July 1, 2005; 11(4): 351 - 356. [Abstract] [Full Text] [PDF]

				V. Gupta, J. L. Carey, H. Kawakubo, A. Muzikansky, J. E. Green, P. K. Donahoe, D. T. MacLaughlin, and S. Maheswaran Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model PNAS, March 1, 2005; 102(9): 3219 - 3224. [Abstract] [Full Text] [PDF]

				E. J. Renaud, D. T. MacLaughlin, E. Oliva, B. R. Rueda, and P. K. Donahoe Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance PNAS, January 4, 2005; 102(1): 111 - 116. [Abstract] [Full Text] [PDF]

				C. Belville, H. Van Vlijmen, C. Ehrenfels, B. Pepinsky, A. R. Rezaie, J.-Y. Picard, N. Josso, N. d. Clemente, and R. L. Cate Mutations of the Anti-Mullerian Hormone Gene in Patients with Persistent Mullerian Duct Syndrome: Biosynthesis, Secretion, and Processing of the Abnormal Proteins and Analysis Using a Three-Dimensional Model Mol. Endocrinol., March 1, 2004; 18(3): 708 - 721. [Abstract] [Full Text] [PDF]

				S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson The Bone Morphogenetic Protein System In Mammalian Reproduction Endocr. Rev., February 1, 2004; 25(1): 72 - 101. [Abstract] [Full Text] [PDF]

				G. Y. Bedecarrats, F. H. O'Neill, E. R. Norwitz, U. B. Kaiser, and J. Teixeira Regulation of gonadotropin gene expression by Mullerian inhibiting substance PNAS, August 5, 2003; 100(16): 9348 - 9353. [Abstract] [Full Text] [PDF]

				G. Murakami, T. Watabe, K. Takaoka, K. Miyazono, and T. Imamura Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads Mol. Biol. Cell, July 1, 2003; 14(7): 2809 - 2817. [Abstract] [Full Text] [PDF]

				L. M. Roberts, J. A. Visser, and H. A. Ingraham Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development Development, March 5, 2003; 129(6): 1487 - 1496. [Abstract] [Full Text] [PDF]

				R. K. Moore, F. Otsuka, and S. Shimasaki Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells J. Biol. Chem., January 3, 2003; 278(1): 304 - 310. [Abstract] [Full Text] [PDF]

				H. Chang, C. W. Brown, and M. M. Matzuk Genetic Analysis of the Mammalian Transforming Growth Factor-{beta} Superfamily Endocr. Rev., December 1, 2002; 23(6): 787 - 823. [Abstract] [Full Text] [PDF]

				U. Valcourt, J. Gouttenoire, A. Moustakas, D. Herbage, and F. Mallein-Gerin Functions of Transforming Growth Factor-beta Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes J. Biol. Chem., September 6, 2002; 277(37): 33545 - 33558. [Abstract] [Full Text] [PDF]

				V. M. Laurich, A. M. Trbovich, F. H. O'Neill, C. P. Houk, P. M. Sluss, A. H. Payne, P. K. Donahoe, and J. Teixeira Mullerian Inhibiting Substance Blocks the Protein Kinase A-Induced Expression of Cytochrome P450 17{alpha}-Hydroxylase/C17-20 Lyase mRNA in a Mouse Leydig Cell Line Independent of cAMP Responsive Element Binding Protein Phosphorylation Endocrinology, September 1, 2002; 143(9): 3351 - 3360. [Abstract] [Full Text] [PDF]

				U. A. Vitt, S. Mazerbourg, C. Klein, and A. J.W. Hsueh Bone Morphogenetic Protein Receptor Type II Is a Receptor for Growth Differentiation Factor-9 Biol Reprod, August 1, 2002; 67(2): 473 - 480. [Abstract] [Full Text] [PDF]

				S. A. Pangas, A. W. Rademaker, D. A. Fishman, and T. K. Woodruff Localization of the Activin Signal Transduction Components in Normal Human Ovarian Follicles: Implications for Autocrine and Paracrine Signaling in the Ovary J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2644 - 2657. [Abstract] [Full Text] [PDF]

				R. L. Jones, L. A. Salamonsen, Y. C. Zhao, J.-F. Ethier, A. E. Drummond, and J. K. Findlay Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization Mol. Hum. Reprod., April 1, 2002; 8(4): 363 - 374. [Abstract] [Full Text] [PDF]

				R. Jaatinen, J. Bondestam, T. Raivio, K. Hilden, L. Dunkel, N. Groome, and O. Ritvos Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin {beta}B-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1254 - 1261. [Abstract] [Full Text] [PDF]

				A. L. L. Durlinger, M. J. G. Gruijters, P. Kramer, B. Karels, T. R. Kumar, M. M. Matzuk, U. M. Rose, F. H. de Jong, J. Th. J. Uilenbroek, J. A. Grootegoed, et al. Anti-Mullerian Hormone Attenuates the Effects of FSH on Follicle Development in the Mouse Ovary Endocrinology, November 1, 2001; 142(11): 4891 - 4899. [Abstract] [Full Text] [PDF]

				J. Teixeira, S. Maheswaran, and P. K. Donahoe Mullerian Inhibiting Substance: An Instructive Developmental Hormone with Diagnostic and Possible Therapeutic Applications Endocr. Rev., October 1, 2001; 22(5): 657 - 674. [Abstract] [Full Text] [PDF]

				T. R. Clarke, Y. Hoshiya, S. E. Yi, X. Liu, K. M. Lyons, and P. K. Donahoe Mullerian Inhibiting Substance Signaling Uses a Bone Morphogenetic Protein (BMP)-Like Pathway Mediated by ALK2 and Induces Smad6 Expression Mol. Endocrinol., June 1, 2001; 15(6): 946 - 959. [Abstract] [Full Text] [PDF]

				D. L. Segev, Y. Hoshiya, A. E. Stephen, M. Hoshiya, T. T. Tran, D. T. MacLaughlin, P. K. Donahoe, and S. Maheswaran Mullerian Inhibiting Substance Regulates NFkappa B Signaling and Growth of Mammary Epithelial Cells in Vivo J. Biol. Chem., July 13, 2001; 276(29): 26799 - 26806. [Abstract] [Full Text] [PDF]

				D. L. Segev, Y. Hoshiya, M. Hoshiya, T. T. Tran, J. L. Carey, A. E. Stephen, D. T. MacLaughlin, P. K. Donahoe, and S. Maheswaran Mullerian-inhibiting substance regulates NF-kappa B signaling in the prostate in vitro and in vivo PNAS, January 8, 2002; 99(1): 239 - 244. [Abstract] [Full Text] [PDF]