Abstract 437: Bmper Regualtes Bmp Signaling Through Endocytosis

Signaling through Bone Morphogenic Proteins (Bmp) governs the patterning of many tissues including the cardiovascular system. Nevertheless, simple models of Bmp regulation are insufficient to explain the divergent and tightly regulated roles of Bmp signaling in development and disease. Bone Morphogenic Protein binding Endothelial cell precursor Regulator (Bmper; Cv2 or crossveinless 2) is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Pro- and anti-Bmp activities have been postulated for extracellular Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. We show here that as molar concentration increases, Bmper dynamically switches from a Bmp4 agonist to one that antagonizes Bmp4-mediated Smad activation. Rather than strictly acting in the extracellular compartment, a molar excess of Bmper to Bmp4 leads to their internalization through an endosomal pathway fated for lysosomal degradation. This Bmp trap and sink mechanism is clathrin-mediated and is dependent on the degree of Bmper proteolysis. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad and MAPK activation and pursuant Bmp-responsive gene transcription in embryonic mesenchyme. As observed in model systems of Bmp signaling, our data indicate that control of sensitivity to Bmp signaling occurs through a complex interplay between Bmper and Chordin. Our observations support a dramatic reconstitution of the existing paradigm for understanding Bmp signaling, one that extends the extracellular activity of selective Bmp modulators to include subcellular regulation. A concentration-dependent molecular switch resolves critical discordances through which Bmper regulates Bmp activity, and has broad implications for Bmp signaling in vivo.