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J. Cell Biol. 184 (4): 597-609

Copyright © 2009 by the Rockefeller University Press.


A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling

Rusty Kelley1, Rongqin Ren1, Xinchun Pi1, Yaxu Wu1, Isabel Moreno1, Monte Willis1, Martin Moser1, Malcolm Ross1, Monika Podkowa2, Liliana Attisano2, , and Cam Patterson1

1 Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599
2 Department of Biochemistry, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada

Correspondence to Cam Patterson: cpatters{at}

Abstract: Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

Abbreviations used in this paper: ES, embryonic stem; HCAEC, human coronary arterial endothelial cell; MEC, mouse endothelial cell; MEF, mouse embryonic fibroblast.

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