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ELife Jun 2022Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA;...
Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; InhβA/InhβA) or activin C (ActC; InhβC/InhβC), or as heterodimers, as with activin AC (ActAC; InhβA:InhβC). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the InhβC chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the InhβC chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins.
Topics: Activin Receptors; Activin Receptors, Type I; Activins; Animals; Ligands; Mice; Signal Transduction
PubMed: 35736809
DOI: 10.7554/eLife.78197 -
Nature Communications Jul 2016Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large...
Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-β1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein.
Topics: Activins; Binding Sites; Crystallography, X-Ray; Follistatin; Growth Differentiation Factor 2; Humans; Models, Molecular; Protein Domains; Protein Precursors; Transforming Growth Factor beta1
PubMed: 27373274
DOI: 10.1038/ncomms12052 -
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 -
Molecular and Cellular Endocrinology Oct 2009There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone... (Review)
Review
There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone mass in vivo. Although Activins and Inhibins were initially isolated from the gonad, Activins are also produced and stored in bone, whereas Inhibins exert their regulation on bone cell differentiation and metabolism via endocrine effects. The accumulating data provide evidence that reproductive hormones, distinct from classical sex steroids, are important regulators of bone mass and bone strength. Given the well described dominant antagonism of Inhibin over Activin, as well as over BMPs and TGFbeta, the gonadally derived Inhibins are important regulators of locally produced osteotrophic factors. Thus, the cycling Inhibins in females and diurnal changes in Inhibin B in males elicit temporal shifts in Inhibin levels (tone) that de-repress the pituitary. This fundamental action has the potential to de-repress locally stimulated changes in osteoblastogenesis and osteoclastogenesis, thereby altering bone metabolism.
Topics: Activins; Animals; Bone Remodeling; Humans; Inhibins; Osteoblasts; Osteoclasts; Osteogenesis
PubMed: 19615428
DOI: 10.1016/j.mce.2009.07.001 -
The Journal of International Medical... 2010In some cancer cell lines, the gene encoding activin A (inhibin βA [INHBA]) is over-expressed and enhances cancer proliferation. Protein levels of activin A and...
In some cancer cell lines, the gene encoding activin A (inhibin βA [INHBA]) is over-expressed and enhances cancer proliferation. Protein levels of activin A and follistatin were assessed in glioblastoma and normal brain tissues in this study, and the effect of activin A and follistatin treatment on the proliferation of U87 human glioblastoma cells in vitro was also studied. High levels of activin A were observed in glioblastomas compared with normal brain tissue. In contrast, follistatin levels were similar between the two tissues. [(3)H]Thymidine assay showed that activin A (3 - 30 ng/ml) produced a dose-dependent increase in DNA synthesis of U87 cells compared with controls. Flow cytometric analyses showed that activin A increased the proliferative index of U87 cells compared with controls. Activin A also induced up-regulation of p-SMAD2/3 in a dose-dependent manner. Treatment of U87 cells with follistatin blocked these activin A-induced effects. The disequilibrium between activin A and follistatin may play a role in the development of glioblastoma.
Topics: Activins; Adult; Aged; Biological Assay; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Female; Flow Cytometry; Follistatin; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Immunohistochemistry; Male; Middle Aged; RNA, Messenger; Smad Proteins; Thymidine; Tritium
PubMed: 20926007
DOI: 10.1177/147323001003800416 -
Methods (San Diego, Calif.) Jun 2014The TGF-β pathway is an evolutionarily conserved signal transduction module that mediates diverse biological processes in animals. In Drosophila, both the BMP and... (Review)
Review
The TGF-β pathway is an evolutionarily conserved signal transduction module that mediates diverse biological processes in animals. In Drosophila, both the BMP and Activin branches are required for viability. Studies rooted in classical and molecular genetic approaches continue to uncover new developmental roles for TGF-β signaling. We present an overview of the secreted ligands, transmembrane receptors and cellular Smad transducer proteins that compose the core pathway in Drosophila. An assortment of tools have been developed to conduct tissue-specific loss- and gain-of-function experiments for these pathway components. We discuss the deployment of these reagents, with an emphasis on appropriate usage and limitations of the available tools. Throughout, we note reagents that are in need of further improvement or development, and signaling features requiring further study. A general theme is that comparison of phenotypes for ligands, receptors, and Smads can be used to map tissue interactions, and to separate canonical and non-canonical signaling activities. Core TGF-β signaling components are subject to multiple layers of regulation, and are coupled to context-specific inputs and outputs. In addition to fleshing out how TGF-β signaling serves the fruit fly, we anticipate that future studies will uncover new regulatory nodes and modes and will continue to advance paradigms for how TGF-β signaling regulates general developmental processes.
Topics: Activins; Animals; DNA-Binding Proteins; Developmental Biology; Drosophila; Gene Expression Regulation, Developmental; Phosphorylation; Signal Transduction; Transforming Growth Factor beta
PubMed: 24680699
DOI: 10.1016/j.ymeth.2014.03.016 -
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 -
Trends in Endocrinology and Metabolism:... Sep 2010Follicle-stimulating hormone (FSH), produced by pituitary gonadotrope cells, is required for maturation of ovarian follicles. The FSHbeta subunit is the limiting factor... (Review)
Review
Follicle-stimulating hormone (FSH), produced by pituitary gonadotrope cells, is required for maturation of ovarian follicles. The FSHbeta subunit is the limiting factor for production of mature hormone and provides biological specificity. Activin dramatically induces FSHbeta transcription and the secondary rise in FSH, important for follicular development, is dependent on this induction. Thus, regulation of FSHbeta levels by activin is crucial for female reproductive fitness. This review discusses activin signaling pathways, transcription factors and FSHbeta promoter elements required for activin responsiveness. Because FoxL2, a forkhead transcription factor, was recently shown to be instrumental in relaying activin signaling to the FSHbeta promoter, we focus in this paper on its role and the inter-relatedness of several key players in activin responsiveness on the FSHbeta promoter.
Topics: Activins; Animals; Female; Follicle Stimulating Hormone, beta Subunit; Forkhead Transcription Factors; Humans; Promoter Regions, Genetic; Signal Transduction
PubMed: 20598900
DOI: 10.1016/j.tem.2010.05.006 -
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 -
Andrology May 2017Activin A is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity. In the adult murine reproductive tract,...
Activin A is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity. In the adult murine reproductive tract, activin A mRNA (Inhba) expression levels are highest in the caput epididymis and decrease progressively towards the distal vas deferens. The activin-binding protein, follistatin (FST), shows the opposite expression pattern, with exceptionally high levels of the Fst288 mRNA variant in the vas deferens. This unique pattern of expression suggests that activin A and follistatin, in particular FST288, play region-specific roles in regulating the epididymis and vas deferens. The cellular distribution of activin and follistatin and structural organization of the male reproductive tract was examined in wild-type and transgenic (TghFST315) mice lacking FST288. Compared to wild-type littermates, TghFST315 mice showed a 50% reduction in serum follistatin and a significant elevation of both activin A and B. Testicular, epididymal and seminal vesicle weights were reduced, but intra-testicular testosterone was normal. A decrease in the epididymal duct diameter in the corpus and thickening of the peritubular smooth muscle in the cauda, together with increased coiling of the proximal vas deferens, were observed in TghFST315 mice. No immune cell infiltrates were detected. Immunohistochemistry indicated that epithelial cells are the main source of activins and follistatin in the epididymis and vas deferens. Activin A, but not activin B, was also localized to sperm heads in the lumen of the epididymis and vas deferens. Expression of Inhba and another immunoregulatory gene, indoleamine-2,3-dioxygenase (Ido-1), was increased approximately twofold in the TghFST315 caput epididymis, but several other genes associated with immunoregulation, inflammation or fibrosis were unaffected. Our novel data indicate that disruption of follistatin expression has significant effects on the testis and epididymis, and suggest an association between activin A and indoleamine-2,3-dioxygenase in the caput epididymis, with implications for the epididymal immunoenvironment.
Topics: Activins; Animals; Follistatin; Genitalia, Male; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Transgenic; Polymerase Chain Reaction
PubMed: 28235253
DOI: 10.1111/andr.12337