Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland. Inhibins/activins are involved in regulating a number of diverse functions such as hypothalamic and pituitary hormone secretion, gonadal hormone secretion, germ cell development and maturation, erythroid differentiation, insulin secretion, nerve cell survival, embryonic axial development or bone growth, depending on their subunit composition. Inhibins appear to oppose the functions of activins.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
The function that stimulates a cell to grow or proliferate. Most growth factors have other actions besides the induction of cell growth or proliferation.
It has been 70 years since the name inhibin was used to describe a gonadal factor that negatively regulated pituitary hormone secretion. The majority of this period was required to achieve purification and definitive characterization of inhibin, an event closely followed by identification and characterization of activin and follistatin (FS). In contrast, the last 15-20 years saw a virtual explosion of information regarding the biochemistry, physiology, and biosynthesis of these proteins, as well as identification of activin receptors, and a unique mechanism for FS action-the nearly irreversible binding and neutralization of activin. Many of these discoveries have been previously summarized; therefore, this review will cover the period from the mid 1990s to present, with particular emphasis on emerging themes and recent advances. As the field has matured, recent efforts have focused more on human studies, so the endocrinology of inhibin, activin, and FS in the human is summarized first. Another area receiving significant recent attention is local actions of activin and its regulation by both FS and inhibin. Because activin and FS are produced in many tissues, we chose to focus on a few particular examples with the most extensive experimental support, the pituitary and the developing follicle, although nonreproductive actions of activin and FS are also discussed. At the cellular level, it now seems that activin acts largely as an autocrine and/or paracrine growth factor, similar to other members of the transforming growh factor beta superfamily. As we discuss in the next section, its actions are regulated extracellularly by both inhibin and FS. In the final section, intracellular mediators and modulators of activin signaling are reviewed in detail. Many of these are shared with other transforming growh factor beta superfamily members as well as unrelated molecules, and in a number of cases, their physiological relevance to activin signal propagation remains to be elucidated. Nevertheless, taken together, recent findings suggest that it may be more appropriate to consider a new paradigm for inhibin, activin, and FS in which activin signaling is regulated extracellularly by both inhibin and FS whereas a number of intracellular proteins act to modulate cellular responses to these activin signals. It is therefore the balance between activin and all of its modulators, rather than the actions of any one component, that determines the final biological outcome. As technology and model systems become more sophisticated in the next few years, it should become possible to test this concept directly to more clearly define the role of activin, inhibin, and FS in reproductive physiology.
The action characteristic of a hormone, any substance formed in very small amounts in one specialized organ or group of cells and carried (sometimes in the bloodstream) to another organ or group of cells in the same organism, upon which it has a specific regulatory action. The term was originally applied to agents with a stimulatory physiological action in vertebrate animals (as opposed to a chalone, which has a depressant action). Usage is now extended to regulatory compounds in lower animals and plants, and to synthetic substances having comparable effects; all bind receptors and trigger some biological process.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
We report here the complete amino acid sequence of the human inhibin beta B-subunit as deduced from the sequence of cDNA and genomic clones. The primary translation product of the beta B mRNA predicts a protein of 407 amino acids, containing a prepro region of 292 amino acids separated by basic amino acids from the mature C-terminal 115 amino acids. Mammalian tissue culture cells transfected with a beta B-subunit expression plasmid secreted an activin B homodimer of approximately 22K mol wt. Coexpression of the beta A- and beta B-subunit mRNAs resulted in the secretion of the three forms of activin, A, AB, and B. Purified activin B was shown to elicit FSH release in an in vitro pituitary assay and trigger the accumulation of hemoglobin in K562 cells. The potency of activin B in both of these assays (ED50 approximately 2 ng/ml) was indistinguishable from that observed for activin A.
TGF-beta ligands stimulate diverse cellular differentiation and growth responses by signaling through type I and II receptors. Ligand antagonists, such as follistatin, block signaling and are essential regulators of physiological responses. Here we report the structure of activin A, a TGF-beta ligand, bound to the high-affinity antagonist follistatin. Two follistatin molecules encircle activin, neutralizing the ligand by burying one-third of its residues and its receptor binding sites. Previous studies have suggested that type I receptor binding would not be blocked by follistatin, but the crystal structure reveals that the follistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif and occupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can be explained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The mode of ligand binding by follistatin has important implications for its ability to neutralize homo- and heterodimeric ligands of this growth factor family.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionUniProtKB
Activins and inhibins belong to the transforming growth factor beta (TGF-beta)-like superfamily and exert their effects on a broad range of cellular targets by modulating cell differentiation and proliferation. Members of this family interact with two structurally related classes of receptors (type I and type II), both containing a serine/threonine kinase domain. When expressed alone, the type II but not the type I activin receptor can bind activin. However, the presence of a type I receptor is required for signaling. For TGF-beta1, ligand binding to the type II receptor results in the recruitment and transphosphorylation of the type I receptor. Transient overexpression of the two types of activin receptor results in ligand-independent receptor heteromerization and activation. Nevertheless, activin addition to the transfected cells increased complex formation between the two receptors, suggesting a mechanism of action similar to that observed for the TGF-beta receptor. In the present study, we generated a stable cell line, overexpressing the two types of activin receptor upon induction, in the human erythroleukemia cell line K562. We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. Using this stable line, we analyzed the effects of activin and inhibin on human erythroid differentiation. Our results indicate that activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. Finally, using cell lines that can be induced to overexpress ActRII and ActRIB or ActRIB only, we show that the inhibin antagonistic effects on activin-induced biological responses are mediated through a competition for the type II activin receptor but also require the presence of an inhibin-specific binding component.
Evidence
2:
Inferred from Physical InteractionUniProtKB
We report here the complete amino acid sequence of the human inhibin beta B-subunit as deduced from the sequence of cDNA and genomic clones. The primary translation product of the beta B mRNA predicts a protein of 407 amino acids, containing a prepro region of 292 amino acids separated by basic amino acids from the mature C-terminal 115 amino acids. Mammalian tissue culture cells transfected with a beta B-subunit expression plasmid secreted an activin B homodimer of approximately 22K mol wt. Coexpression of the beta A- and beta B-subunit mRNAs resulted in the secretion of the three forms of activin, A, AB, and B. Purified activin B was shown to elicit FSH release in an in vitro pituitary assay and trigger the accumulation of hemoglobin in K562 cells. The potency of activin B in both of these assays (ED50 approximately 2 ng/ml) was indistinguishable from that observed for activin A.
Evidence
3:
Inferred from Physical InteractionUniProtKB
Modulation of activin and other TGF beta superfamily signaling is the primary mechanism of action for both follistatin (FS) and FS-like 3 (FSTL-3). However, most studies of these ligands use activin A due to its wide availability. We have now tested the ability of FS288 and FSTL-3 to bind and neutralize activin B relative to activin A. Activin B bound to both FS and FSTL-3 at a potency approximately 10-fold lower than that of activin A. Moreover, whereas both activins had similar biological activity in 293 cell reporter assays, FS and FSTL-3 were approximately 3-fold more effective in neutralizing activin A relative to activin B. These results suggest that neutralization of activins A and B by FS and FSTL-3 are not identical, so that the relative activity of each activin in tissues where both are produced, such as in the ovary, could be quite different. In addition, biological systems that use primarily activin B, but which have been examined in vitro using activin A, may need to be reevaluated to determine the actual physiologic roles of FS or FSTL-3.
J. Biol. Chem. 270, 6308-6313 (1995)[PubMed:7890768]
The beta:beta activin homodimer and alpha:beta inhibin heterodimer are mutual antagonists which share a common beta subunit. Recently, it has been shown that, similar to transforming growth factor-beta 1, activin is an inhibitor of hepatocyte DNA synthesis. The activin receptor appears to be an obligatory complex of genetically distinct type I and II transmembrane serine/threonine kinases. Activin type I receptors, SKR1 and SKR2, were first cloned from well differentiated human hepatoma cells (HepG2). This prompted us to investigate the binding of activin and inhibin to receptors from HepG2 cells and the effect of the two ligands on DNA synthesis. Here we show that beta:beta activin binds to the activin type II receptor kinase (ActRII) which induces activin binding to the type I receptor kinase SKR2 to form ActRII.beta:beta.SKR2 complexes in which an activin beta chain occupies each receptor subunit. Inhibin also binds to ActRII through its beta subunit, competes with the binding of activin to ActRII, but fails to form the ActRII.SKR2 complex. No specific binding site for inhibin could be demonstrated in HepG2 cells. Inhibin, which had no activity of its own, antagonized the inhibitory effect of activin on DNA synthesis. The results suggest that inhibin may be a natural antagonist of assembly of the heterodimeric activin receptor complex through a dominant-negative mechanism.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
The process in which relatively unspecialized cells, e.g. embryonic or regenerative cells, acquire specialized structural and/or functional features that characterize the cells, tissues, or organs of the mature organism or some other relatively stable phase of the organism's life history. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
A series of molecular signals initiated by activation of a receptor on the surface of a cell. The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a cholesterol stimulus.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a follicle-stimulating hormone stimulus.
Reactions, triggered in response to the presence of a foreign body or the occurrence of an injury, which result in restriction of damage to the organism attacked or prevention/recovery from the infection caused by the attack.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
The regulatory control of human erythropoiesis through a purified protein, activin A, was examined. Previous studies using mixed populations of bone marrow cells suggested that activin A has an indirect effect on cellular proliferation and DNA synthesis of erythroid progenitors through the mediation of accessory cells. In present studies, the cultures of purified erythroid progenitors were used to examine the effect of activin A on globin gene expression. Human erythroid burst-forming units (BFU-E) were partially purified from peripheral blood, and after 8 days of culture the cells generated consisted mainly of erythroid colony-forming units (CFU-E). It was found that the subsequent 7-day cultures of these purified progenitors yielded similar numbers and size distributions of erythroid colonies, regardless of the presence of activin A in the cultures. In addition, these erythroid progenitor cells were responsive, in terms of stimulation of DNA synthesis, to the addition of erythropoietin, but not to treatment by activin A. Therefore, once the erythroid progenitors are depleted of accessory cells, activin A has little effect on both the proliferation and the DNA synthesis of these progenitors. However, when these purified erythroid progenitors were cultured in the presence of activin A, the levels of all alpha, beta, and epsilon globin transcripts and hemoglobins were significantly increased. In addition, disuccinimidyl suberate was found to chemically cross-link 125I-activin A to cell surface binding proteins (45 to 54 Kd) in both purified erythroid progenitors and K562 cells. The labeling of these binding proteins was specifically inhibited by the presence of unlabeled activin A, but not transforming growth factor-beta. These results suggest that, in addition to its indirect effect on DNA synthesis and cellular proliferation of erythroid progenitors, activin A directly affects the levels of globin mRNAs and hemoglobins in developing human erythroid cells through its specific surface binding receptor(s).
The progression of the eyelid in a camera-type eye from its formation to the mature state. The eyelid is a membranous cover that helps protect and lubricate the eye.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
The process whose specific outcome is the progression of the hair follicle over time, from its formation to the mature structure. A hair follicle is a tube-like opening in the epidermis where the hair shaft develops and into which the sebaceous glands open.
Evidence
1:
Inferred from Genetic InteractionUniProtKB
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
The process in which precursor cell type acquires the specialized features of a hematopoietic progenitor cell, a class of cell types including myeloid progenitor cells and lymphoid progenitor cells.
Several years ago, we cloned and characterized from a B cell leukemia a new secreted protein which, on the basis of its high degree of structural homology with follistatin, was defined as a member of the follistatin family and accordingly named follistatin-related gene (FLRG). However, follistatin and FLRG revealed non-overlapping patterns of expression in various tissues thereby indicating the existence of non-redundant functional roles for these proteins throughout the organism. As known for a long time, follistatin is a biological regulator of activin and bone morphogenetic protein (BMP) function in various cellular systems: in particular, it inhibits the effects of activin on hematopoiesis. We therefore investigated the expression and effects of FLRG during human hematopoiesis with particular focus on the effect of this soluble glycoprotein in the regulation of erythropoiesis. For this purpose, we have for the first time, compared the role of Activin A, BMP2 and BMP4 during erythropoiesis, in primary human cells. Our results indicate that, BMP2 acts on early erythroid cells while Activin A acts on a more differentiated population. We report the induction by Activin A and BMP2 of cell commitment towards erythropoiesis in the absence of EPO. This induction involves two key events: increase of EPO-R and the decrease of GATA2 expression. Our results indicate that despite their high structural homology, follistatin and FLRG do not regulate the same signaling targets, therefore highlighting distinct functions and mechanisms for these two proteins in the human hematopoietic system. We thus propose a working model for the regulation of activin or BMP-induced human erythropoiesis by follistatin/FLRG.
The chemical reactions and pathways resulting in the formation of hemoglobin, an oxygen carrying, conjugated protein containing four heme groups and globin.
The regulatory control of human erythropoiesis through a purified protein, activin A, was examined. Previous studies using mixed populations of bone marrow cells suggested that activin A has an indirect effect on cellular proliferation and DNA synthesis of erythroid progenitors through the mediation of accessory cells. In present studies, the cultures of purified erythroid progenitors were used to examine the effect of activin A on globin gene expression. Human erythroid burst-forming units (BFU-E) were partially purified from peripheral blood, and after 8 days of culture the cells generated consisted mainly of erythroid colony-forming units (CFU-E). It was found that the subsequent 7-day cultures of these purified progenitors yielded similar numbers and size distributions of erythroid colonies, regardless of the presence of activin A in the cultures. In addition, these erythroid progenitor cells were responsive, in terms of stimulation of DNA synthesis, to the addition of erythropoietin, but not to treatment by activin A. Therefore, once the erythroid progenitors are depleted of accessory cells, activin A has little effect on both the proliferation and the DNA synthesis of these progenitors. However, when these purified erythroid progenitors were cultured in the presence of activin A, the levels of all alpha, beta, and epsilon globin transcripts and hemoglobins were significantly increased. In addition, disuccinimidyl suberate was found to chemically cross-link 125I-activin A to cell surface binding proteins (45 to 54 Kd) in both purified erythroid progenitors and K562 cells. The labeling of these binding proteins was specifically inhibited by the presence of unlabeled activin A, but not transforming growth factor-beta. These results suggest that, in addition to its indirect effect on DNA synthesis and cellular proliferation of erythroid progenitors, activin A directly affects the levels of globin mRNAs and hemoglobins in developing human erythroid cells through its specific surface binding receptor(s).
Activins, members of a family of the transforming growth factor beta (TGF beta), are involved in the regulation of multiple biological events. We found a novel effect of activin A on hybridoma and myeloma cell lines. Activin A exhibited a cytotoxic effect on interleukin-6 (IL-6)-dependent B9 cells and induced a significant increase in the proportion of fragmented DNA. B9 cells exposed to activin A released high amounts of lactate dehydrogenase (LDH) and exhibited the typical ladder pattern of DNA fragmentation of apoptotic cells. IL-6 did not prevent apoptosis of B9 cells induced by activin A. The cytotoxicity of activin A to B9 cells was suppressed by follistatin. On the other hand, TGF beta showed no cytotoxic effect on B9 cells. These findings indicate that apoptosis induced by activin A could be one of the mechanisms to prevent uncontrolled cell growth.
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
Signaling of TGFbeta family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFbeta-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.
Proc. Natl. Acad. Sci. U.S.A. 85, 2434-2438 (1988)[PubMed:3267209]
We have isolated a protein that exhibits a potent differentiation-inducing activity toward mouse Friend erythroleukemia (MEL) cells and human K-562 cells. The protein, designated erythroid differentiation factor (EDF), was found in the culture fluid of human THP-1 cells that had been treated with phorbol 12-myristate 13-acetate. EDF is a homodimer with a Mr of 25,000; the Mr of the monomer is 15,500. cDNA clones encoding the Mr 15,500 subunit of EDF from THP-1 libraries were isolated and sequenced. Surprisingly, the sequence of EDF mRNA is identical to that for the beta A subunit of inhibin, a gonadal protein that suppresses the secretion of pituitary follicle-stimulating hormone. Southern blot analysis indicates that only one gene for EDF/inhibin beta A exists in the human genome. When the EDF subunit cDNA was linked to a simian virus 40 expression vector containing the dihydrofolate reductase gene and transfected into Chinese hamster ovary dihydrofolate reductase negative cells, the transformants began to secrete EDF, demonstrating that the cDNA actually encoded the EDF subunit.
Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of interferon-gamma.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
The process whose specific outcome is the progression of a tooth or teeth over time, from formation to the mature structure(s). A tooth is any hard bony, calcareous, or chitinous organ found in the mouth or pharynx of an animal and used in procuring or masticating food.
Evidence
1:
Inferred from Genetic InteractionUniProtKB
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
J. Endocrinol. 153, 221-230 (1997)[PubMed:9166111]
Monoclonal antibodies, specific for the beta A and beta B subunits of activin, were used to develop a new two-site ELISA for activin-AB. The assay had a detection limit of 0.19 ng/ml. High concentrations of activin-AB were found in bovine, ovine and porcine follicular fluids (FF), with less in human FF (1310, 1730, 688 and 7 ng/ml respectively). Recovery of spiked activin-AB standard from human, bovine and ovine FFs and from homogenized human placental extracts averaged 91%, 115%, 115% and 94% respectively. Within-plate coefficients of variation for different concentration of activin-AB were between 1.3% and 2.67%. The between-plate coefficient of variation was 5.5%. Cross-reactivity experiments showed the high specificity of the assay for activin-AB, with inhibin-A, inhibin-B, follistatin, activin-A and activin-B all cross-reacting < 0.2%. Incubation with high concentrations of follistatin (500 ng/ml) prior to assay did not affect the recovery of activin-AB. Samples of bovine, porcine, ovine and human FF gave dose responses parallel to that of the standard, as did bovine granulosa cell-conditioned media. In human and porcine FF, levels of activin-A and activin-AB were similar whereas, in bovine and ovine FF, activin-A levels were approximately threefold higher than activin-A, nearly all of the endogenous activin-AB in bovine FF was detected in the eluate from gel permeation chromatography with an M(r) of > 700000 indicating its association with higher molecular weight binding protein(s). By contrast, after denaturation, immunoreactive activin-AB was detected with an M(r) of approximately 25000 consistent with the complete dissociation from binding proteins. Activin-A was detected in relatively high concentrations in human FF (approximately 5 ng/ml), homogenized placental extracts (4.35-95.5 ng/g), sera from pregnant women (> 4 ng/ml) and amniotic fluid (3-13 ng/ml), and in much lower concentrations in postmenopausal serum (500 pg/ ml), normal cycle serum (100-200 pg/ml), serum from gonadotrophin-treated women (200 pg/ml), and normal adult male serum (225 pg/ml). Activin-A was also found in the culture media from explants of human amnion, chorion, maternal decidua and placenta. In marked contrast, activin-AB was undetectable (< 0.19 ng/ml) in all of these samples with the exception of human FF (approximately 7 ng/ml). In conclusion, we have developed a sensitive and specific ELISA to measure total (bound+free) activin-AB. Preliminary results show a more restricted distribution of this isoform compared with activin-A. The presence of high levels of both activin-A and activin-AB in FF suggests a function for both isoforms in the developing ovarian follicle.
Evidence
2:
Inferred from Genetic InteractionUniProtKB
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
The biological process whose specific outcome is the progression of the palate from an initial condition to its mature state. This process begins with the formation of the structure and ends with the mature structure. The palate is the partition that separates the nasal and oral cavities.
Evidence
1:
Inferred from Genetic InteractionUniProtKB
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
Activins and inhibins belong to the transforming growth factor beta (TGF-beta)-like superfamily and exert their effects on a broad range of cellular targets by modulating cell differentiation and proliferation. Members of this family interact with two structurally related classes of receptors (type I and type II), both containing a serine/threonine kinase domain. When expressed alone, the type II but not the type I activin receptor can bind activin. However, the presence of a type I receptor is required for signaling. For TGF-beta1, ligand binding to the type II receptor results in the recruitment and transphosphorylation of the type I receptor. Transient overexpression of the two types of activin receptor results in ligand-independent receptor heteromerization and activation. Nevertheless, activin addition to the transfected cells increased complex formation between the two receptors, suggesting a mechanism of action similar to that observed for the TGF-beta receptor. In the present study, we generated a stable cell line, overexpressing the two types of activin receptor upon induction, in the human erythroleukemia cell line K562. We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. Using this stable line, we analyzed the effects of activin and inhibin on human erythroid differentiation. Our results indicate that activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. Finally, using cell lines that can be induced to overexpress ActRII and ActRIB or ActRIB only, we show that the inhibin antagonistic effects on activin-induced biological responses are mediated through a competition for the type II activin receptor but also require the presence of an inhibin-specific binding component.
Activin A, a cytokine member of the transforming growth factor-beta superfamily, is expressed locally by the mesenchymal component of the hemopoietic microenvironment. Its expression is regulated on the mRNA level by different cytokines, and the biological activity of the protein is tightly controlled by several inhibitory molecules. Activin A affects hemopoietic cells of various lineages, as evidenced by in vitro studies of leukemia and lymphoma cell lines, which were used to elucidate the mechanism of its action. In the B-cell lineage, activin A is a cell cycle inhibitor, a mediator of apoptosis, and a cytokine antagonist. Limited information is available on the effects of activin A on normal hemopoietic cells. Recent studies suggest that it might be a negative regulator of normal B lymphopoiesis. Whereas the functions of activin A in vitro are well established, further research tools are needed to elucidate its role within specific hemopoietic microenvironments in vivo.
Any process that activates or increases the frequency, rate or extent of ovulation, the release of a mature ovum/oocyte from an ovary.
ISSOrtholog Curator
Positive regulation of pathway-restricted SMAD protein phosphorylationdefinition[GO:0010862]
Any process that increases the rate, frequency or extent of pathway-restricted SMAD protein phosphorylation. Pathway-restricted SMAD proteins and common-partner SMAD proteins are involved in the transforming growth factor beta receptor signaling pathways.
Endoglin, a transmembrane glycoprotein that acts as a transforming growth factor-beta (TGF-beta) coreceptor, is downregulated in PC3-M metastatic prostate cancer cells. When restored, endoglin expression in PC3-M cells inhibits cell migration in vitro and attenuates the tumorigenicity of PC3-M cells in SCID mice, though the mechanism of endoglin regulation of migration in prostate cancer cells is not known. The current study indicates that endoglin is phosphorylated on cytosolic domain threonine residues by the TGF-beta type I receptors ALK2 and ALK5 in prostate cancer cells. Importantly, in the presence of constitutively active ALK2, endoglin did not inhibit cell migration, suggesting that endoglin phosphorylation regulated PC3-M cell migration. Therefore, our results suggest that endoglin phosphorylation is a mechanism with relevant functional consequences in prostate cancer cells. These data demonstrate for the first time that TGF-beta receptor-mediated phosphorylation of endoglin is a Smad-independent mechanism involved in the regulation of prostate cancer cell migration.
The three distinct types of kidneys, pronephros, mesonephros and metanephros, develop consecutively in vertebrates. The earliest form of embryonic kidney, the pronephros, is derived from intermediate mesoderm and the first expressed genes localized in the pronephros anlage are the transcription factors osr1, osr2, hnf1b, lhx1 and pax8, here referred to as the early nephrogenic transcription factors. However, the pathway inducing nephrogenesis and the network of theses factors are poorly understood. Treatment of the undifferentiated animal pole explant (animal cap) of Xenopus with activin A and retinoic acid induces pronephros formation providing a powerful tool to analyze key molecular events in nephrogenesis.
Activin is known to play an important regulatory role in reproduction, including pregnancy. To further examine the role and signaling mechanism of activin in regulating placental function, the steady-state level of activin type I receptor (ActRI) mRNA in immortalized extravillous trophoblasts (IEVT) cells was measured using competitive PCR (cPCR). An internal standard of ActRI cDNA for cPCR was constructed for the quantification of ActRI mRNA levels in IEVT cells. ActRI mRNA levels were increased in a dose-dependent manner by activin-A with the maximal effect observed at the dose of 10 ng/ml. Time course studies revealed that activin-A had maximal effects on ActRI mRNA levels at 6 hours after treatment. The effects of activin-A on ActRI mRNA levels was blocked by follistatin, an activin binding protein, in a dose-dependent manner. In addition, inhibin-A inhibited basal, as well as activin-A-induced ActRI mRNA levels. These findings provide evidence, for the first time, that activin-A modulates ActRI mRNA levels in human trophoblast cells.
The three distinct types of kidneys, pronephros, mesonephros and metanephros, develop consecutively in vertebrates. The earliest form of embryonic kidney, the pronephros, is derived from intermediate mesoderm and the first expressed genes localized in the pronephros anlage are the transcription factors osr1, osr2, hnf1b, lhx1 and pax8, here referred to as the early nephrogenic transcription factors. However, the pathway inducing nephrogenesis and the network of theses factors are poorly understood. Treatment of the undifferentiated animal pole explant (animal cap) of Xenopus with activin A and retinoic acid induces pronephros formation providing a powerful tool to analyze key molecular events in nephrogenesis.
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
Activins transduce their signals by binding to activin type I receptors and activin type II receptors, both of which contain a serine/threonine kinase domain. In this study, we established stable transfectants expressing two types of activin receptors, ActRI and ActRIB, to clarify the role of these receptors in activin signalling for growth inhibition in HS-72 mouse B-cell hybridoma cells. Over-expression of ActRI suppressed activin A-induced cell-cycle arrest in the G1 phase caused by inhibition of retinoblastoma protein phosphorylation through induction of p21CIP1/WAF1, a cyclin-dependent kinase inhibitor, and subsequent apoptosis. In contrast, HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. These results indicate that ActRI and ActRIB are distinct from each other and that the ActRI/ActRIB expression ratio could regulate cell-cycle arrest in the G1 phase and subsequent apoptosis in HS-72 cells induced by activin A.
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.
Signaling of TGFbeta family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFbeta-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.
Protein which, by binding to a cell-surface receptor, triggers an intracellular signal-transduction pathway leading to differentiation, proliferation, or other cellular response.
Protein which functions as a hormone, a biochemical substance secreted by specialized cells that affects the metabolism or behavior of other cells which possess functional receptors for the hormone. Hormones may be hydrophilic, like insulin, in which case the receptors are on the cell surface, or lipophilic, like the steroids, where the receptor can be intracellular.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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