BMPR2 inhibits activin- and BMP-signaling via wild type ALK2

Abstract

TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also may signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.