Inhibins and activins were initially recognized as gonadal protein hormones which reciprocally modulate follicle stimulating hormone production by the anterior pituitary. This Project played a key roll in the initial characterization of these dimeric proteins which share a common subunit. Activins are now recognized to be produced by and exert important endocrine, paracrine and autocrine actions in reproductive and other tissues to regulate cell proliferation, development and differentiated functions. Inhibin (alphabeta) opposes some but not all actions of activin (betabeta) and both are structural and functional members of the transforming growth factor beta (TGFbeta) superfamily of growth and differentiation factors. Similar to TGFbeta, activins signal through two classes of membrane receptors. During the last grant period we cloned and characterized the Type II receptor for activin (ActRII), and thereby discovered the first vertebrate receptor serine kinase (RSK) as well as the first receptor for any member of the TGFbeta superfamily. The field has now identified over a dozen RSK family members including a second Type II activin receptor, the Type II activin receptor, the Type II TGFbeta receptor and Type I receptors for both activin and TGFbeta.
The first aim of this Project is to examine the nature of the interactions between the Type I and Type II activin receptors and to examine the roles played by the dimeric ligand in both complex (involving activin and both the Type I and II receptors) formation, cis and trans receptor phosphorylation and signalling.
The second aim proposes to clone and characterize the components of the inhibin receptor and then to explore several hypotheses concerning the mechanisms by which inhibin blocks activin. The importance of this interaction has been convincingly demonstrated by reports of the appearance of gonadal and other tumors in 100% of mice whose ability to produce inhibin had been abolished by deletion of the inhibin alpha gene. During the past grant period we proposed that activin produced locally in the pituitary was a key modulator of gonadotrope functions and uncovered multiple regulatory loops involving locally produced activin and follistatin, an activin binding protein.
Aim 3 will examine the regulation of Type I and Type II activin receptors in the anterior pituitary. The board spectrum of critical biological actions of these hormones/growth factors and their possible applications to the treatment of reproductive, bone, hematopoietic and central nervous system disorders forms a compelling rationale for the exploration of their receptors, signalling mechanisms and local regulatory roles.
| 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 |
| Blount, Amy L; Vaughan, Joan M; Vale, Wylie W et al. (2008) A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem 283:7016-26 |
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