Activin plays a critical role in the regulation of reproduction. It also controls cell growth and differentiation in diverse processes such as mesoderm induction during embryogenesis, nerve cell survival, bone formation and wound repair. This Project proposes to characterize the binding surfaces on activin and its receptors. We will employ site-directed mutagenesis to generate ligand and receptor mutants with disrupted or altered binding properties. In addition, activin mutants that compete with the binding of wild-type activin to its receptors and/or follistatin will be developed and tested for their effects on the bioavailability of endogenous activin. The structure of Bone Morphogenetic Protein 2 (BMP-2) bound to its type IA receptor soluble extracellular domain (BRIA-ECD) has been published and Project II of this Program has recently solved the structure of BMP-7 in complex with the activin type II receptor extracellular domain (ActRII-ECD). These crystal structures will enable the use of amino acid sequence comparisons and computer modeling approaches to predict residues critical for activin:receptor binding. Defining the residues constituting the binding interfaces between activin and its receptors will allow rational design of bioactive activin analogs and small molecule activin agonists or antagonists. These reagents will have therapeutic potential based on their ability to mimic or block activin actions including its effects on reproductive function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1)
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Salk Institute for Biological Studies
La Jolla
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Muenster, Uwe; Korupolu, Radhika; Rastogi, Ratindra et al. (2011) Antagonism of activin by activin chimeras. Vitam Horm 85:105-28
Kim, Meejung; Choe, Senyon (2011) BMPs and their clinical potentials. BMB Rep 44:619-34
Looyenga, Brendan D; Wiater, Ezra; Vale, Wylie et al. (2010) Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24:608-20
Valera, Elvira; Isaacs, Michael J; Kawakami, Yasuhiko et al. (2010) BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One 5:e11167
Isaacs, Michael J; Kawakami, Yasuhiko; Allendorph, George P et al. (2010) Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly. Mol Endocrinol 24:1469-77
Hassold, Terry; Hunt, Patricia (2009) Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 21:703-8
Wiater, Ezra; Lewis, Kathy A; Donaldson, Cynthia et al. (2009) Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes. Mol Endocrinol 23:1033-42
Cheng, Edith Y; Hunt, Patricia A; Naluai-Cecchini, Theresa A et al. (2009) Meiotic recombination in human oocytes. PLoS Genet 5:e1000661
Ciarmela, Pasquapina; Wiater, Ezra; Smith, Sean M et al. (2009) Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology 150:906-14
Ciarmela, Pasquapina; Wiater, Ezra; Vale, Wylie (2008) Activin-A in myometrium: characterization of the actions on myometrial cells. Endocrinology 149:2506-16

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