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Fertility and Sterility Mar 1996To review the available information regarding the polypeptide factors inhibin, activin, and follistatin in reproductive physiology. (Review)
Review
OBJECTIVE
To review the available information regarding the polypeptide factors inhibin, activin, and follistatin in reproductive physiology.
DESIGN
The protein structure, tissue expression, regulation, and effects of these factors are outlined, with an emphasis on the reproductive tissues in both females and males. Although some information is only available in animal model systems, human data has been selected whenever possible.
CONCLUSIONS
Inhibin and activin are closely related peptides with opposing actions, whereas follistatin is a structurally unrelated peptide that may act indirectly through modulation of inhibin-activin effects. These three peptides are secreted in highest levels by the adult gonads; however, they are also present in a wide variety of reproductive and nonreproductive tissues where they are believed to exert local, tissue-specific effects. Within the reproductive system, these peptides play a role in the regulation of gonadotropin biosynthesis and secretion, ovarian and placental steroidogenesis, and oocyte and spermatogonial maturation.
Topics: Activins; Animals; Follistatin; Glycoproteins; Growth Substances; Humans; Inhibins; Reproduction
PubMed: 8774270
DOI: 10.1016/s0015-0282(16)58137-0 -
Journal of Mother and Child Jun 2023Within the endocrine-paracrine signalling network at the maternal-foetal interface, the activin-inhibin-follistatin system modulates extravillous trophoblast invasion,... (Review)
Review
BACKGROUND
Within the endocrine-paracrine signalling network at the maternal-foetal interface, the activin-inhibin-follistatin system modulates extravillous trophoblast invasion, suggesting a potential role in preeclampsia pathogenesis. This study aimed to compile the evidence published in the last decade regarding the variation in maternal serum activins, inhibin- and follistatin-related proteins in preeclamptic pregnancies compared to healthy pregnancies, and to discuss their role in predicting and understanding the pathophysiology of preeclampsia.
MATERIAL AND METHODS
A scoping review was conducted in MEDLINE, EMBASE and LILACS databases to identify studies published within the last ten years (2012-2022).
RESULTS
Thirty studies were included. None of the studies addressed maternal serum changes of isoforms different from activin A, inhibin A, follistatin, and follistatin-like 3. Sixteen studies evaluated the potential of these isoforms in predicting preeclampsia through the area under the curve from a receiver operating characteristic curve.
CONCLUSIONS
In preeclampsia, inhibin A is upregulated in all trimesters, whereas activin A increases exclusively in the late second and third trimesters. Serum follistatin levels are reduced in women with preeclampsia during the late second and third trimesters. However, changes in follistatin-like 3 remain inconclusive. Inhibin A and activin A can potentially serve as biomarkers of early-onset preeclampsia based on the outcomes of the receiver operating characteristic curve analysis. Further investigations are encouraged to explore the feasibility of quantifying maternal serum levels of activin A and inhibin A as a clinical tool in early preeclampsia prediction.
Topics: Pregnancy; Female; Humans; Follistatin; Follistatin-Related Proteins; Pre-Eclampsia; Inhibins; Activins
PubMed: 37595293
DOI: 10.34763/jmotherandchild.20232701.d-23-00002 -
BMC Cancer Sep 2022Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are...
PURPOSE
Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs.
METHODS
Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression.
RESULTS
Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4 T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4 T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs.
CONCLUSION
In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4 cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.
Topics: Humans; Activins; Adenocarcinoma; Cytokines; Esophageal Neoplasms; Inhibin-beta Subunits; Inhibins; Prognosis; Retrospective Studies; Stomach
PubMed: 36064338
DOI: 10.1186/s12885-022-10016-5 -
Stem Cells (Dayton, Ohio) Jul 2023Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human-induced pluripotent stem cells (iPSCs), yet...
Modulation of WNT, Activin/Nodal, and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation.
Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human-induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation, and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal, and MAPK signaling pathways by stage-specific addition of small-molecule regulators CHIR99021, SB431542, and LY294002, respectively, and measured the impact on hematoendothelial formation in culture. Manipulation of these pathways provided a synergy sufficient to enhance formation of arterial hemogenic endothelium (HE) relative to control culture conditions. Importantly, this approach significantly increased production of human HSPCs with self-renewal and multilineage differentiation properties, as well as phenotypic and molecular evidence of progressive maturation in culture. Together, these findings provide a stepwise improvement in human iPSC differentiation protocols and offer a framework for manipulating intrinsic cellular cues to enable de novo generation of human HSPCs with functionality in vivo.
Topics: Humans; Induced Pluripotent Stem Cells; Activins; Hemangioblasts; Cell Differentiation; Signal Transduction
PubMed: 37220178
DOI: 10.1093/stmcls/sxad040 -
BMC Biology Feb 2022Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal...
BACKGROUND
Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal to distinct Smad branches; activins signal mainly to Smad2/3, while BMPs activate mainly Smad1/5/8. This gives rise to the possibility that competition between the different type I receptors through which activin and BMP signal for common type II receptors can provide a mechanism for fine-tuning the cellular response to activin/BMP stimuli. Among the transforming growth factor-β superfamily type II receptors, ACVR2A/B are highly promiscuous, due to their ability to interact with different type I receptors (e.g., ALK4 vs. ALK2/3/6) and with their respective ligands [activin A (ActA) vs. BMP9/2]. However, studies on complex formation between these full-length receptors situated at the plasma membrane, and especially on the potential competition between the different activin and BMP type I receptors for a common activin type II receptor, were lacking.
RESULTS
We employed a combination of IgG-mediated patching-immobilization of several type I receptors in the absence or presence of ligands with fluorescence recovery after photobleaching (FRAP) measurements on the lateral diffusion of an activin type II receptor, ACVR2A, to demonstrate the principle of competition between type I receptors for ACVR2. Our results show that ACVR2A can form stable heteromeric complexes with ALK4 (an activin type I receptor), as well as with several BMP type I receptors (ALK2/3/6). Of note, ALK4 and the BMP type I receptors competed for binding ACVR2A. To assess the implications of this competition for signaling output, we first validated that in our cell model system (U2OS cells), ACVR2/ALK4 transduce ActA signaling to Smad2/3, while BMP9 signaling to Smad1/5/8 employ ACVR2/ALK2 or ACVR2/ALK3. By combining ligand stimulation with overexpression of a competing type I receptor, we showed that differential complex formation of distinct type I receptors with a common type II receptor balances the signaling to the two Smad branches.
CONCLUSIONS
Different type I receptors that signal to distinct Smad pathways (Smad2/3 vs. Smad1/5/8) compete for binding to common activin type II receptors. This provides a novel mechanism to balance signaling between Smad2/3 and Smad1/5/8.
Topics: Activins; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Ligands; Smad Proteins; Transforming Growth Factor beta
PubMed: 35177083
DOI: 10.1186/s12915-022-01252-z -
Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells.Biomolecules Nov 2022The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in...
The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-β type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-β signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-β superfamily ligands in endometrial cells in vitro.
Topics: Female; Humans; Activins; Endometriosis; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Smad3 Protein; Transforming Growth Factor beta; Receptors, Transforming Growth Factor beta; Activin Receptors, Type I
PubMed: 36551177
DOI: 10.3390/biom12121749 -
The Journal of Endocrinology Jul 2009Activin was discovered in the 1980s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the... (Review)
Review
Activin was discovered in the 1980s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades, many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly and by extracellular antagonists. Over the past 5 years, a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3, as well as identification of activin's roles in gonadal sex development, follicle development, luteolysis, beta-cell proliferation and function in the islet, stem cell pluripotency and differentiation into different cell types and in immune cells. These advances are reviewed to provide perspective for future studies.
Topics: Activins; Animals; Female; Gene Expression Regulation; Humans; Luteolysis; Male; Ovarian Follicle; Sex Determination Processes; Stem Cells; Structure-Activity Relationship; Testis
PubMed: 19273500
DOI: 10.1677/JOE-08-0549 -
Molecular and Cellular Biochemistry Oct 2022Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as... (Review)
Review
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.
Topics: Activins; Bone Morphogenetic Proteins; Drug Development; Humans; Ligands; Mutation; Myositis Ossificans; Ossification, Heterotopic; Transforming Growth Factor beta
PubMed: 35536530
DOI: 10.1007/s11010-022-04446-9 -
Molecular and Cellular Endocrinology Aug 2012Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other... (Review)
Review
Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other members of this large family of pleiotropic factors, play prominent roles in the regulation of diverse biological processes in both differentiated and embryonic stem cells. They have an essential role in maintaining tissue homeostasis in the adult and are known to contribute to the developmental programs in the embryo. Activins are further implicated in the growth and metastasis of tumor cells. Through distinct modes of action, inhibins and follistatins function as antagonists of activin and several other TGF-β family members, including a subset of BMPs/GDFs, and modulate cellular responses and the signaling cascades downstream of these ligands. In the pituitary, the activin pathway is known to regulate key aspects of gonadotrope functions and also exert effects on other pituitary cell types. As in other tissues, activin is produced locally by pituitary cells and acts locally by exerting cell-type specific actions on gonadotropes. These local actions of activin on gonadotropes are modulated by the autocrine/paracrine actions of locally secreted follistatin and by the feedback actions of gonadal inhibin. Knowledge about the mechanism of activin, inhibin and follistatin actions is providing information about their importance for pituitary function as well as their contribution to the pathophysiology of pituitary adenomas. The aim of this review is to highlight recent findings and summarize the evidence that supports the important functions of activin, inhibin and follistatin in the pituitary.
Topics: Activins; Animals; Follistatin; Forkhead Box Protein L2; Forkhead Transcription Factors; Gonadotrophs; Humans; Inhibins; Pituitary Gland; Signal Transduction; TGF-beta Superfamily Proteins
PubMed: 22330643
DOI: 10.1016/j.mce.2012.01.025 -
Journal of Alzheimer's Disease : JAD 2021Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In... (Review)
Review
Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.
Topics: Activins; Adiponectin; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Humans
PubMed: 33814453
DOI: 10.3233/JAD-210206