title: Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding.
abstract: Transforming growth factor-β (TGF-β) family ligands are pleiotropic cytokines. Their physiological activities are not determined by a simple coupling of stimulus and response, but depend critically on context, i.e. the interplay of receptors, ligands, and regulators that form the TGF-β signal transduction system of a cell or tissue. How these different components combine to regulate signaling activities remains poorly understood. Here, we describe a ligand-mediated mechanism of signaling regulation. Based on the observation that the type II TGF-β family receptors ActRIIA, ActRIIB, and BMPRII interact with a large group of overlapping ligands at overlapping epitopes, we hypothesized high affinity ligands compete with low affinity ligands for receptor binding and signaling. We show activin A and other high affinity ligands directly inhibited signaling by the low affinity ligands BMP-2, BMP-7, and BMP-9. We demonstrate activin A functions as a competitive inhibitor that blocks the ligand binding epitope on type II receptors. We propose binding competition and signaling antagonism are integral functions of the TGF-β signal transduction system. These functions could help explain how activin A modulates physiological signaling during extraordinary cellular responses, such as injury and wound healing, and how activin A could elicit disease phenotypes such as cancer-related muscle wasting and fibrosis.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1319.
authors.forename: Senem
authors.initials: S
authors.lastname: Aykul
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1319 emh@msu.edu.
authors.forename: Erik
authors.initials: E
authors.lastname: Martinez-Hackert
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D028341:Activins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D038681:Follistatin / Q000494:pharmacology; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C541386:BMP10 protein, human; C525718:BMP2 protein, human; C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D038681:Follistatin; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D008024:Ligands; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: activin; bone morphogenetic protein (BMP); inhibition mechanism; receptor tyrosine kinase; signal transduction; signaling; transforming growth factor β (TGF-B)