Abstract
Activins and inhibins1, structurally related members of the TGF-β superfamily of growth and differentiation factors2, are mutually antagonistic regulators of reproductive and other functions1,3. Activins bind specific type II receptor serine kinases (ActRII or IIB)4,5,6 to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7,8,9), which then regulates gene expression by activating Smad proteins2. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin9,10,11. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action9,12,13. Here we show that the type III TGF-β receptor, betaglycan14,15, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand–receptor sensitivity, selectivity and function16,17,18,19.
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References
Vale, W. et al. Chemical and biological characterization of the inhibin family of protein hormones. Rec. Prog. Hormone Res. 44, 1–34 (1988).
Massagué, J. TGF-beta signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).
Matzuk, M. M. et al. Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development. Rec. Prog. Horm. Res. 51, 123–154; discussion 155–127 (1996).
Mathews, L. S. & Vale, W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65, 973–982 (1991).
Mathews, L. S., Vale, W. W. & Kintner, C. R. Cloning of a second type of activin receptor and functional characterization in Xenopus embryos. Science 255, 1702–1705 (1992).
Attisano, L., Wrana, J. L., Cheifetz, S. & Massagué, J. Novel activin receptors: distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell 68, 97–108 (1992).
Attisano, L., Wrana, J. L., Montalvo, E. & Massagué, J. Activation of signalling by the activin receptor complex. Mol. Cell. Biol. 16, 1066–1073 (1996).
Carcamo, J. et al. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. Mol. Cell. Biol. 14, 3810–3821 (1994).
Lebrun, J. -J. & Vale, W. W. Activin and inhibin have antagonistic effects on ligand-dependent heterodimerization of the type I and type II activin receptors and human erythroid differentiation. Mol. Cell. Biol. 17, 1682–1691 (1997).
Xu, J. M., McKeehan, K., Matsuzaki, K. & McKeehan, W. L. Inhibin antagonizes inhibition of liver cell growth by activin by a dominant-negative mechanism. J. Biol. Chem. 270, 6308–6313 (1995).
Martens, J. W. et al. Inhibin interferes with activin signaling at the level of the activin receptor complex in Chinese hamster ovary cells. Endocrinology 138, 2928–2936 (1997).
Draper, L. B. et al. Identification of an inhibin receptor in gonadal tumors from inhibin α-subunit knockout mice. J. Biol. Chem. 273, 398–403 (1998).
Hertan, R., Farnworth, P. G., Fitzsimmons, K. L. & Robertson, D. M. Identification of high affinity binding sites for inhibin on ovine pituitary cells in culture. Endocrinology 140, 6–12 (1999).
Lopez-Casillas, F. et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell 67, 785–795 (1991).
Wang, X. F. et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell 67, 797–805 (1991).
Schlessinger, J., Lax, I. & Lemmon, M. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 83, 357–360 (1995).
Tsuda, M., Kamimura, K., Nakato, H. & Selleck, S. The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. Nature 400, 276–280 (1999).
Gunn, T. M. et al. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398, 152–156 (1999).
Nagle, D. et al. The mahogany protein is a receptor involved in suppression of obesity. Nature 398, 148–152 (1999).
Lopez-Casillas, F., Wrana, J. L. & Massague, J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73, 1435–1444 (1993).
Kananen, K. et al. Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/Simian virus t-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol. Endocrinol. 9, 616–627 (1995).
Turgeon, J. L., Kimura, Y., Waring, D. W. & Mellon, P. L. Steroid and pulsatile gonadotropin-releasing hormone (GnRH) regulation of luteinizing hormone and GnRH receptor in a novel gonadotrope cell line. Mol. Endocrinol. 10, 439–450 (1996).
Graham, K. E., Nusser, K. D. & Low, M. J. LβT2 gonadotroph cells secrete follicle stimulating hormone (FSH) in response to activin A. J. Endocrinol. 162, R1–5 (1999).
Hsueh, A. J. W. et al. Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis. Proc. Natl Acad. Sci. USA 84, 5082–5086 (1987).
Woodruff, T. K., Krummen, L., McCray, G. & Mather, J. P. In situ ligand binding of recombinant human [I-125] Activin-A and recombinant human [I-125] Inhibin-A to the adult rat ovary. Endocrinology 133, 2998–3006 (1993).
Alak, B. M., Smith, G. D., Woodruff, T. K., Stouffer, R. L. & Wolf, D. P. Enhancement of primate oocyte maturation and fertilization in vitro by inhibin A and activin A. Fertil. Steril. 66, 646–653 (1996).
Schubert, D. et al. Activin is a nerve cell survival molecule. Nature 344, 868–870 (1990).
Bilezikjian, L. M., Blount, A. L., Campen, C. A., Gonzalez-Manchon, C. & Vale, W. W. Activin-A inhibits proopiomelanocortin messenger RNA accumulation and adrenocorticotropin secretion of AtT20 cells. Mol. Endocrinol. 5, 1389–1395 (1991).
Gray, P. C. et al. Identification of a Binding Site on the Type II Activin Receptor for Activin and Inhibin. J. Biol. Chem. 275, 3206–3212 (2000).
MacConell, L. A., Widger, A. E., Barth-Hall, S. & Roberts, V. J. Expression of activin and follistatin in the rat hypothalamus: anatomical association with gonadotropin-releasing hormone neurons and possible role of central activin in the regulation of luteinizing hormone release. Endocrine 9, 233–241 (1998).
Acknowledgements
We thank K. Kunitake for assistance with binding assays and M. Perrin for helpful discussions. The rat betaglycan cDNA and anti-betaglycan antiserum were provided by J. Massagué and the KK-1 cell line was provided by A. Hsueh. The LβT2 cell line was provided by P. Mellon. This work was supported by the Foundation for Medical Research, California Division and a George E. Hewitt Foundation for Medical Research fellowship to P.G.
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Lewis, K., Gray, P., Blount, A. et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404, 411–414 (2000). https://doi.org/10.1038/35006129
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DOI: https://doi.org/10.1038/35006129
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