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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{triangledown} ,{dagger}

Anke Hartung,1,{ddagger} Keren Bitton-Worms,2,{ddagger} Maya Mouler Rechtman,2 Valeska Wenzel,1 Jan H. Boergermann,3 Sylke Hassel,3 Yoav I. Henis,2 and Petra Knaus1,3*

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.

* Corresponding author. Mailing address: Institute for Chemistry/Biochemistry, FU Berlin, Thielallee 63, 14195 Berlin, Germany. Phone: 49 (0)30-838 52935. Fax: 49 (0)30-838 51935. E-mail: knaus{at}chemie.fu-berlin.de.

{triangledown} Published ahead of print on 21 August 2006.

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

{ddagger} These authors contributed equally to the manuscript.

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.



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