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

Oddrun Elise Olsen,Ingerid Nesthus,Hanne Hella,Toril Holien,Ingemar Turesson,Anders Sundan,Anders Waage,Karin Fahl Wader,Anne Kærsgaard Mylin

doi:10.1186/s12964-015-0104-z

Abstract

BackgroundActivins 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.ResultsIn 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.ConclusionsWe propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-015-0104-z) contains supplementary material, which is available to authorized users.

Highlights

Activins are members of the transforming growth factor (TGF)-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue
Using myeloma cell lines with well-characterized bone morphogenetic proteins (BMPs)-receptor expression and responses, we found that activin A inhibited signaling by BMP-6 and BMP-9 by
Using myeloma cell lines as a model system, we show that activin A antagonizes BMP-6 or BMP-9-signaling through ACVR2A/ACVR2B/ALK2, but not BMP-2 or BMP-4-signaling through BMPR2/ALK3 or BMPR2/ALK6

Summary

Introduction

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. The ligands are divided into subgroups based upon their activation of different SMAD proteins and include TGF-β, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activins and inhibins. Ligands of the TGF-β family signal through type 1 and type 2 receptors that are conserved single transmembrane serine/threonine kinase receptors. These receptors dimerize upon ligand binding and the specificity of the ligand is commonly determined by the binding to the type 2 receptor. TGF-β and activins signal through SMAD2/3, whereas BMPs signal through SMAD1/5/8, this is determined by which of the type 1 receptors that is present in the ligand-bound signaling complex. For example TGF-β can activate both SMAD2/3 and SMAD1/5/8 after binding heteromeric complexes that contain both ALK5 and ALK1 type 1 receptors [1]

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