Inhibin-A Antagonizes TGFβ2 Signaling by Down-Regulating Cell Surface Expression of the TGFβ Coreceptor Betaglycan
Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.Molecular Endocrinology (Impact Factor: 4.02). 02/2010; 24(3):608-20. DOI: 10.1210/me.2008-0374
Inhibin is an atypical member of the TGFbeta family of signaling ligands and is classically understood to function via competitive antagonism of activin ligand binding. Inhibin-null (Inha-/-) mice develop both gonadal and adrenocortical tumors, the latter of which depend upon gonadectomy for initiation. We have previously shown that gonadectomy initiates adrenal tumorigenesis in Inha-/- mice by elevating production of LH, which drives aberrant proliferation and differentiation of subcapsular adrenocortical progenitor cells. In this study, we demonstrate that LH signaling specifically up-regulates expression of TGFbeta2 in the subcapsular region of the adrenal cortex, which coincides with regions of aberrant Smad3 activation in Inha-/- adrenal glands. Consistent with a functional interaction between inhibin and TGFbeta2, we further demonstrate that recombinant inhibin-A antagonizes signaling by TGFbeta2 in cultured adrenocortical cells. The mechanism of this antagonism depends upon the mutual affinity of inhibin-A and TGFbeta2 for the signaling coreceptor betaglycan. Although inhibin-A cannot physically displace TGFbeta2 from its binding sites on betaglycan, binding of inhibin-A to the cell surface causes endocytic internalization of betaglycan, thereby reducing the number of available binding sites for TGFbeta2 on the cell surface. The mechanism by which inhibin-A induces betaglycan internalization is clathrin independent, making it distinct from the mechanism by which TGFbeta ligands themselves induce betaglycan internalization. These data indicate that inhibin can specifically antagonize TGFbeta2 signaling in cellular contexts where surface expression of betaglycan is limiting and provide a novel mechanism for activin-independent phenotypes in Inha-/- mice.
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- "Activin (M r ∼25,000) is a disulphide-linked dimer of two inhibin subunits which stimulates pituitary FSH release and FSH mRNA accumulation . Activin exerts its function by signaling through hetero-tetrameric complexes composed of activin-type II receptors (ActRII or ActRIIB); while the symmetrical structure of activin allows it to form complete hetero-tetrameric receptor complexes , the asymmetrical structure of inhibin allows it to only bind to the ActRII/IIB components, resulting in competitive inhibition . Follistatin is a monomeric, cysteine-rich glycoprotein (M r ∼31,000–49,000; based on alternative mRNA splicing and variable glycosylation), which although structurally unrelated to inhibin suppresses pituitary FSH release in a manner similar to inhibin. "
ABSTRACT: Inhibin and follistatin are known to reduce fecundity by inhibiting the actions of activin and FSH. Thus, the immunoneutralization of these hormones is a rational proposal for augmenting reproductive performance. The present study describes a comprehensive computational methodology comprising of a consensus approach of several B- and Th-cell epitope prediction tools for the identification of epitopic regions within the structure of these hormones that can be incorporated into a poly-epitope fecundity vaccine. The proposed peptide (RGD-WSPAALRLLQRPPEEPA-KK-YSFPISSILE) should be effective in multiple animal species, generating good immunological memory.
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- "In addition, TβRIII binds inhibins with high affinity, potentiating the exclusion of ACTRIB (ALK4) to antagonize activin-mediated functions , –. Also, TβRIII enables inhibins to antagonize BMP signaling  and to reduce TGF-β2 signals through the endocytic internalization of TβRIII . Conversely, TβRIII also allow TGF-β1 and 2 to attenuate inhibin-mediated functions by downregulating the expression and binding of this co-receptor , . "
ABSTRACT: TGF-β type III receptor (TβRIII) is a coreceptor for TGFβ family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-β -, bone morphogenetic proteins (BMP2/4) and inhibins regulate different checkpoints during T cell differentiation. Although TβRIII is expressed on hematopoietic cells, the role of this receptor in the immune system remains elusive. Here, we provide the first evidence that TβRIII is developmentally expressed during T cell ontogeny, and plays a crucial role in thymocyte differentiation. Blocking of endogenous TβRIII in fetal thymic organ cultures led to a delay in DN-DP transition. In addition, in vitro development of TβRIII(-/-) thymic lobes also showed a significant reduction in absolute thymocyte numbers, which correlated with increased thymocyte apoptosis, resembling the phenotype reported in Inhibin α (-/-) thymic lobes. These data suggest that Inhibins and TβRIII may function as a molecular pair regulating T cell development.
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- "This function of betaglycan was independent of TGF␤ stimulation, which suggests that inhibins may act via betaglycan instead to regulate motility in ovarian epithelial cells. This pathway may play a similar role in other inhibin target tissues such as adrenal (Looyenga et al., 2010) and endometrium (Florio et al., 2005), although generally betaglycan's role in mediating inhibin action in these tissues is not well-defined. Betaglycan also appears to act as a tumor suppressor in many other tissues, as well, broadly inhibiting the development of metastatic features; most often, this role has been linked to betaglycan's role as a TGF␤ accessory receptor (extensively reviewed elsewhere, see Gatza et al., 2010; Stenvers and Findlay, 2010). "
ABSTRACT: Betaglycan is a co-receptor for the TGFβ superfamily, particularly important in establishing the potency of its ligands on their target cells. In recent years, new insights have been gained into the structure and function of betaglycan, expanding its role from that of a simple co-receptor to include additional ligand-dependent and ligand-independent roles. This review focuses on recent advances in the betaglycan field, with a particular emphasis on its newly discovered actions in mediating the trafficking of TGFβ superfamily receptors and as a determinant of the functional output of TGFβ superfamily signalling. In addition, this review encompasses a discussion of the emerging roles of the betaglycan/inhibin pathway in reproductive cancers and disease.
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