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      Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

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          Abstract

          Background

          Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease.

          Results

          In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6.

          Conclusions

          We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12964-015-0104-z) contains supplementary material, which is available to authorized users.

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          Most cited references 17

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          Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling.

          Transforming growth factor-beta (TGFbeta) regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways. Activin receptor-like kinase-1 (ALK1) induces Smad1/5 phosphorylation, leading to an increase in endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes. Here, we report that ALK5 is important for TGFbeta/ALK1 signaling; endothelial cells lacking ALK5 are deficient in TGFbeta/ALK1-induced responses. More specifically, we show that ALK5 mediates a TGFbeta-dependent recruitment of ALK1 into a TGFbeta receptor complex and that the ALK5 kinase activity is required for optimal ALK1 activation. TGFbeta type II receptor is also required for ALK1 activation by TGFbeta. Interestingly, ALK1 not only induces a biological response opposite to that of ALK5 but also directly antagonizes ALK5/Smad signaling.
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            Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis.

            Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.
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              Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity.

              In the accompanying paper, we show that the expression of a dominant negative activin receptor can convert prospective ectoderm into neural tissue, which suggests that activin is an inhibitor of neuralization. Here we report the isolation and characterization of an activin antagonist, follistatin, that can induce neural tissue directly in vivo. Follistatin RNA is localized in the Spemann organizer and notochord, tissues known to be potent neural inducers. We demonstrate that follistatin RNA and protein are able to block the activity of activin in embryonic explants. Furthermore, we show that follistatin RNA directly neuralizes ectodermal explants in the absence of detectable mesoderm. Thus, follistatin is present at the correct time and location to play a role in neural induction in vivo.
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                Author and article information

                Contributors
                oddrun.e.olsen@ntnu.no
                Karin.Inger.Martina.Fahl.Wader@stolav.no
                hanne.hella@ntnu.no
                anne.k.mylin@dadlnet.dk
                ingemar.turesson@med.lu.se
                inesthus@broadpark.no
                anders.waage@ntnu.no
                anders.sundan@ntnu.no
                toril.holien@ntnu.no
                Journal
                Cell Commun Signal
                Cell Commun. Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                6 June 2015
                6 June 2015
                2015
                : 13
                Affiliations
                [ ]K.G. Jebsen Center for Myeloma Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Post box 8905, MTFS, N-7491 Trondheim, Norway
                [ ]Departments of Oncology, and Hematology, St. Olav’s University Hospital, Trondheim, Norway
                [ ]Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
                [ ]Department of Hematology and Coagulation Disorders, Skane University Hospital, Malmö, Sweden
                [ ]Department of Medicine, Haukeland University Hospital, Bergen, Norway
                [ ]Departments of Hematology, St. Olav’s University Hospital, Trondheim, Norway
                [ ]CEMIR (Centre of Molecular Inflammation Research), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
                Article
                104
                10.1186/s12964-015-0104-z
                4467681
                26047946
                © Olsen et al. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Cell biology

                activin a, follistatin, receptor, bmp, bone morphogenetic proteins, myeloma

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