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      Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B.

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          Abstract

          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.

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          Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis.

          Rajasekhar Suragani, Samuel M Cadena, Sharon Cawley … (2014)
          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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            Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling.

            Stefan Karlsson, Jonas Larsson, Peter ten Dijke … (2003)
            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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              Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity.

              Ali H. Brivanlou, Amy D. Melton, O. d'Allivy Kelly (1994)
              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

                Journal
                Journal ID (iso-abbrev): Cell Commun. Signal
                Title: Cell communication and signaling : CCS
                Publisher: Springer Nature
                ISSN (Electronic): 1478-811X
                ISSN (Print): 1478-811X
                Publication date (Electronic): Jun 06 2015
                Volume: 13
                Affiliations
                [1 ] 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. oddrun.e.olsen@ntnu.no.
                [2 ] Departments of Oncology, and Hematology, St. Olav's University Hospital, Trondheim, Norway. Karin.Inger.Martina.Fahl.Wader@stolav.no.
                [3 ] 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. hanne.hella@ntnu.no.
                [4 ] Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. anne.k.mylin@dadlnet.dk.
                [5 ] Department of Hematology and Coagulation Disorders, Skane University Hospital, Malmö, Sweden. ingemar.turesson@med.lu.se.
                [6 ] Department of Medicine, Haukeland University Hospital, Bergen, Norway. inesthus@broadpark.no.
                [7 ] 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. anders.waage@ntnu.no.
                [8 ] Departments of Hematology, St. Olav's University Hospital, Trondheim, Norway. anders.waage@ntnu.no.
                [9 ] 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. anders.sundan@ntnu.no.
                [10 ] CEMIR (Centre of Molecular Inflammation Research), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. anders.sundan@ntnu.no.
                [11 ] 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. toril.holien@ntnu.no.
                Article
                Publisher Item ID: 10.1186/s12964-015-0104-z
                DOI: 10.1186/s12964-015-0104-z
                PMC ID: 4467681
                PubMed ID: 26047946
                SO-VID: 4026c3d0-6a86-4bbf-b6c2-f286b294787c
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