Although activins were discovered by virtue of their capacity to stimulate the production of
follicle-stimulating hormone by the pituitary gland and inhibins were initially characterized as FSH
inhibitors, activins and inhibins are dimeric proteins that share a common subunit. There are 3 activins (A, B, and A-B),
comprising different combinations of 2 closely related beta subunits (beta-A/beta-A; beta-B/beta-B; and beta-A/beta-B,
respectively) and 2 inhibins (A and B), consisting of 1 beta-subunit and an inhibin-specific alpha subunit (alpha/beta-A
and alpha/beta-B). Activins impinge on a much broader spectrum of cells than do inhibins; however, in those systems in
which both proteins are functional, they have opposing biologic effects. Activins are members of a family of
polypeptide growth factors that includes also the transforming growth factors-beta,
mullerian duct-inhibiting substance, and several bone morphogenetic proteins.
Mathews and Vale (1991) cloned an activin receptor cDNA by use of a method that has been used to clone other
receptors, such as that for erythropoietin. The cloning was based on the ability of the receptor to bind a labeled ligand
following expression of a cDNA library in mammalian cells. The cDNA coded for a protein of 494 amino acids
comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase
domain with predicted serine/threonine specificity. On the basis of affinity-crosslinking studies, They identified 2 types of activin receptors. The type I receptor has a molecular size of 65 kD, while the molecular
size of the type II receptor is 85 kD.
NCBI Summary:
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Type II receptors are considered to be constitutively active kinases. This gene encodes activin A type IIB receptor, which displays a 3- to 4-fold higher affinity for the ligand than activin A type II receptor. [provided by RefSeq, Jul 2008]
General function
Receptor
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Cellular localization
Plasma membrane
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Ovarian function
Follicle development, Antral follicle growth, Steroid metabolism, Germ cell development
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Activin decoy receptor ActRIIB:Fc lowers FSH and therapeutically restores oocyte yield, prevents oocyte chromosome misalignments and spindle aberrations, and increases fertility in midlife female SAMP8 mice. Bernstein LR et al. (2015) Women of advanced maternal age (AMA, age ≥35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with eCG for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that whereas eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG co-treatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response, and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways, and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.//////////////////
da Silva SJ, et al reported the expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation.
The formation of the essential functional unit of the ovary, the primordial follicle, occurs during fetal life in humans. Factors regulating oogonial proliferation and interaction with somatic cells before primordial follicle formation are largely unknown. We have investigated the expression, localisation and functional effects of activin and its receptors in the human fetal ovary at 14-21 weeks gestation. Expression of mRNA for the activin betaA and betaB subunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR. Expression of betaA mRNA increased 2-fold across the gestational range examined. Activin subunits and receptors were localised by immunohistochemistry. The betaA subunit was expressed by oogonia, and the betaB subunit and activin receptors were expressed by both oogonia and somatic cells. betaA expression was increased in larger oogonia at later gestations, but was low in oocytes within newly formed primordial follicles. Treatment of ovary fragments with activin A in vitro increased both the number of oogonia present and oogonial proliferation, as detected by bromodeoxyuridine (BrdU) incorporation. These data indicate that activin may be involved in the autocrine and paracrine regulation of germ cell proliferation in the human ovary during the crucial period of development leading up to primordial follicle formation.
Expression regulated by
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Ovarian localization
Granulosa, Luteal cells
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Eramaa M, et al 1995 reported the expression of activin receptor mRNAs in cultured human granulosa-luteal cells.
Northern blot analysis indicated that cultured human GL cells as well as
freshly isolated preovulatory granulosa cells express the specific mRNAs for all
currently known serine/threonine kinase activin receptors, i.e. activin receptors I,
IB, II, and IIB.