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Molecular and Cellular Biology, October 2006, p. 7791-7805, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00022-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Different Routes of Bone Morphogenic Protein (BMP) Receptor Endocytosis Influence BMP Signaling ^,

Anke Hartung,^1, Keren Bitton-Worms,^2, Maya Mouler Rechtman,² Valeska Wenzel,¹ Jan H. Boergermann,³ Sylke Hassel,³ Yoav I. Henis,² and Petra Knaus^1,3*

Department of Physiological Chemistry II, University of Wuerzburg, Wuerzburg, Germany,¹ Department of Neurobiochemistry, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel,² Institute for Biochemistry, FU Berlin, Berlin, Germany³

Received 5 January 2006/ Returned for modification 6 March 2006/ Accepted 31 July 2006

Endocytosis is important for a variety of functions in eukaryotic cells, including the regulation of signaling cascades via transmembrane receptors. The internalization of bone morphogenetic protein (BMP) receptor type I (BRI) and type II (BRII) and its relation to signaling were largely unexplored. Here, we demonstrate that both receptor types undergo constitutive endocytosis via clathrin-coated pits (CCPs) but that only BRII undergoes also caveola-like internalization. Using several complementary approaches, we could show that (i) BMP-2-mediated Smad1/5 phosphorylation occurs at the plasma membrane in nonraft regions, (ii) continuation of Smad signaling resulting in a transcriptional response requires endocytosis via the clathrin-mediated route, and (iii) BMP signaling leading to alkaline phosphatase induction initiates from receptors that fractionate into cholesterol-enriched, detergent-resistant membranes. Furthermore, we show that BRII interacts with Eps15R, a constitutive component of CCPs, and with caveolin-1, the marker protein of caveolae. Taken together, the localization of BMP receptors in distinct membrane domains is prerequisite to their taking different endocytosis routes with specific impacts on Smad-dependent and Smad-independent signaling cascades.

Published ahead of print on 21 August 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to the manuscript.

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