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 a 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. This gene encodes activin A type IB receptor, composed of 11 exons. Alternative splicing and alternative polyadenylation result in 3 fully described transcript variants. The mRNA expression of variants 1, 2, and 3 is confirmed, and a potential fourth variant contains an alternative exon 8 and lacks exons 9 through 11, but its mRNA expression has not been confirmed.
Mukasa C, et al 2003 reported that Activin Signaling through Type IB Activin Receptor Stimulates Aromatase Activity in the Ovarian Granulosa Cell-Like Human Granulosa (KGN) Cells.
In addition to a stimulatory effect on FSH production by the pituitary gland, activin is thought to have a paracrine or autocrine role in follicular development in the ovary, where it is produced. Recently, we established a human ovarian granulosa tumor cell line, KGN, which possesses in vivo characteristics of granulosa cells, namely the expression of functional FSH receptors and cytochrome P-450 aromatase. Here, we have demonstrated the activin signaling pathway and its role in KGN cells. A series of transient transfection experiments revealed that activin type IB receptor (ActRIB) is an essential component of the activin signaling pathway in KGN cells. Smad2 was found to act downstream of ActRIB as an intracellular signal transmitter. Smad7, but not Smad6, was an inhibitory Smad in the pathway. Finally, we show that FSH receptor expression and cytochrome P-450 (P-450) aromatase activity was up-regulated by activin stimulation through ActRIB in KGN cells. These results show that we have clarified the signaling mechanisms and the roles of activin in the human granulosa cell line, KGN. Activin signaling mediated by ActRIB-Smad2 system in the ovary may thus be essential for the regulation of follicular differentiation.
Expression regulated by
LH, mir145
Comment
MicroRNA-145 suppresses mouse granulosa cell proliferation by targeting activin receptor IB. Yan G et al. MicroRNAs (miRNAs) are a class of 21- to 25-nucleotide non-coding RNAs, some of which are important gene regulators involved in folliculogenesis. In this study, we used CCK-8, real-time PCR and Western blot assays to demonstrate that miR-145 inhibits mouse granulosa cell (mGC) proliferation. Combined with the results of luciferase reporter assays that studied the 3'-untranslated region of ACVRIB mRNA, these assays identified ACVRIB as a direct target of miR-145. The ectopic expression of miR-145 reduced the levels of both ACVRIB mRNA and protein and also interfered with activin-induced Smad2 phosphorylation. Altogether, this study revealed that miR-145 suppresses mGC proliferation by targeting ACVRIB.
Gene expression increased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.
Ovarian localization
Granulosa, Luteal cells
Comment
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.
Izadyar F, et al reported immunohistochemical localization and mRNA expression of
activin, inhibin, follistatin, and activin receptor in bovine
cumulus-oocyte complexes (COC)during in vitro maturation.
Activin receptor immunoreactivity in cumulus cell membranes and
oolemma increased during oocyte maturation to maximum values at the end of
culture in most of the COCs. It is concluded that the consistent presence of activin
and the increase in activin receptor in cumulus cells and oocytes during in vitro
maturation indicate a paracrine and/or autocrine action for activin on bovine
oocyte maturation.