Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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

Copyright © 2009 by the Rockefeller University Press.


Article

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}med.unc.edu

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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model.
K. Komatsu, A. Shimada, T. Shibata, S. Wada, H. Ideno, K. Nakashima, N. Amizuka, M. Noda, and A. Nifuji (2013)
J. Endocrinol. 219, 145-158
   Abstract »    Full Text »    PDF »
The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation.
H. Cao, A. Jheon, X. Li, Z. Sun, J. Wang, S. Florez, Z. Zhang, M. T. McManus, O. D. Klein, and B. A. Amendt (2013)
Development 140, 3348-3359
   Abstract »    Full Text »    PDF »
Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation.
J. Heinke, M. Juschkat, A. Charlet, L. Mnich, T. Helbing, C. Bode, C. Patterson, and M. Moser (2013)
J. Cell Sci. 126, 3082-3094
   Abstract »    Full Text »    PDF »
Quantitative kinetics analysis of BMP2 uptake into cells and its modulation by BMP antagonists.
H. Alborzinia, H. Schmidt-Glenewinkel, I. Ilkavets, K. Breitkopf-Heinlein, X. Cheng, P. Hortschansky, S. Dooley, and S. Wolfl (2013)
J. Cell Sci. 126, 117-127
   Abstract »    Full Text »    PDF »
Bmper Inhibits Endothelial Expression of Inflammatory Adhesion Molecules and Protects Against Atherosclerosis.
X. Pi, P. Lockyer, L. A. Dyer, J. C. Schisler, B. Russell, S. Carey, D. T. Sweet, Z. Chen, E. Tzima, M. S. Willis, et al. (2012)
Arterioscler Thromb Vasc Biol 32, 2214-2222
   Abstract »    Full Text »    PDF »
Osteoblast-like Differentiation of Cultured Human Coronary Artery Smooth Muscle Cells by Bone Morphogenetic Protein Endothelial Cell Precursor-derived Regulator (BMPER).
S. Satomi-Kobayashi, M. Kinugasa, R. Kobayashi, K. Hatakeyama, Y. Kurogane, T. Ishida, N. Emoto, Y. Asada, Y. Takai, K.-i. Hirata, et al. (2012)
J. Biol. Chem. 287, 30336-30345
   Abstract »    Full Text »    PDF »
LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the Bmp System in Endothelial Cells and in Angiogenesis.
X. Pi, C. E. Schmitt, L. Xie, A. L. Portbury, Y. Wu, P. Lockyer, L. A. Dyer, M. Moser, G. Bu, E. J. Flynn III, et al. (2012)
Circ. Res. 111, 564-574
   Abstract »    Full Text »    PDF »
Crossveinless d is a vitellogenin-like lipoprotein that binds BMPs and HSPGs, and is required for normal BMP signaling in the Drosophila wing.
J. Chen, S. M. Honeyager, J. Schleede, A. Avanesov, A. Laughon, and S. S. Blair (2012)
Development 139, 2170-2176
   Abstract »    Full Text »    PDF »
BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium.
T. Helbing, R. Rothweiler, E. Ketterer, L. Goetz, J. Heinke, S. Grundmann, D. Duerschmied, C. Patterson, C. Bode, and M. Moser (2011)
Blood 118, 5040-5049
   Abstract »    Full Text »    PDF »
BMPing Up Angiogenesis via BMPER.
D. A. Prosdocimo and M. K. Jain (2011)
Arterioscler Thromb Vasc Biol 31, 2167-2168
   Full Text »    PDF »
Bone Morphogenetic Protein Endothelial Cell Precursor-Derived Regulator Regulates Retinal Angiogenesis In Vivo in a Mouse Model of Oxygen-Induced Retinopathy.
I. Moreno-Miralles, R. Ren, M. Moser, M. E. Hartnett, and C. Patterson (2011)
Arterioscler Thromb Vasc Biol 31, 2216-2222
   Abstract »    Full Text »    PDF »
Sortilin Associates with Transforming Growth Factor-{beta} Family Proteins to Enhance Lysosome-mediated Degradation.
S. Kwon and J. L. Christian (2011)
J. Biol. Chem. 286, 21876-21885
   Abstract »    Full Text »    PDF »
BMPER Is Upregulated by Statins and Modulates Endothelial Inflammation by Intercellular Adhesion Molecule-1.
T. Helbing, R. Rothweiler, J. Heinke, L. Goetz, P. Diehl, A. Zirlik, C. Patterson, C. Bode, and M. Moser (2010)
Arterioscler Thromb Vasc Biol 30, 554-560
   Abstract »    Full Text »    PDF »
Kruppel-like factor 15 regulates BMPER in endothelial cells.
T. Helbing, F. Volkmar, U. Goebel, J. Heinke, P. Diehl, H. L. Pahl, C. Bode, C. Patterson, and M. Moser (2010)
Cardiovasc Res 85, 551-559
   Abstract »    Full Text »    PDF »
The extracellular regulation of bone morphogenetic protein signaling.
D. Umulis, M. B. O'Connor, and S. S. Blair (2009)
Development 136, 3715-3728
   Abstract »    Full Text »    PDF »
Bmper sticker sends Bmp to lysosomes.
B. Short (2009)
J. Cell Biol. 184, 465
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882