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J. Biol. Chem., Vol. 278, Issue 44, 43755-43763, October 31, 2003

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The Erythropoietin Receptor Transmembrane Domain Mediates Complex Formation with Viral Anemic and Polycythemic gp55 Proteins^*

Stefan N. Constantinescu¶||, Tzvia Keren¶**, William P. Russ, Iban Ubarretxena-Belandia, Yaniv Malka**, Katharina F. Kubatzky, Donald M. Engelman, Harvey F. Lodish¶¶, and Yoav I. Henis**||||

From the Ludwig Institute for Cancer Research and University of Louvain, Brussels B-1200, Belgium, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, the ^**Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, and the ^¶¶Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Erythropoietin receptor (EpoR) activation is crucial for mature red blood cell production. The murine EpoR can also be activated by the envelope protein of the polycythemic (P) spleen focus forming virus (SFFV), gp55-P. Due to differences in the TM sequence, gp55 of the anemic (A) strain SFFV, gp55-A, cannot efficiently activate the EpoR. Using antibody-mediated immunofluorescence co-patching, we show that the majority of EpoR forms hetero-oligomers at the cell surface with gp55-P and, surprisingly, with gp55-A. The EpoR TM domain is targeted by gp55-P and -A, as only chimeric receptors containing EpoR TM sequences oligomerized with gp55 proteins. Both gp55-P and gp55-A are homodimers on the cell surface, as shown by co-patching. However, when the homomeric interactions of the isolated TM domains were assayed by TOXCAT bacterial reporter system, only the TM sequence of gp55-P was dimerized. Thus, homo-oligomerization of gp55 proteins is insufficient for full EpoR activation, and a correct conformation of the dimer in the TM region is required. This is supported by the failure of gp55-AP, a mutant protein whose TM domain can homo-oligomerize, to fully activate EpoR. As unliganded EpoR forms TM-dependent but inactive homodimers, we propose that the EpoR can be activated to different extents by homodimeric gp55 proteins, depending on the conformation of the gp55 protein dimer in the TM region.

Received for publication, March 24, 2003 , and in revised form, August 8, 2003.

^* This work was supported in part by a grant from the Israeli Ministry of Health Chief Scientist's Office and the Public Committee for Estate Funds, Israel Ministry of Justice (to Y. I. H.), by Grant GM54160 from the National Institutes of Health, grants from the National Foundation for Cancer Research (to D. M. E.), Grant HL32262 from the National Institutes of Health (to H. F. L.), grants from The Medical Foundation, Boston, the Belgian Federation against Cancer, and the Fonds National de la Recherche Scientifique, Belgium (to S. N. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

Delori postdoctoral fellow of the Institute of Cellular Pathology, Brussels, Belgium.

^|||| Incumbent of the Zalman Weinberg Chair in Cell Biology. To whom correspondence may be addressed: Dept. of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: 972-3-640-9053; Fax: 972-3-640-7643; E-mail: henis{at}post.tau.ac.il.

^|| To whom correspondence may be addressed: Ludwig Institute for Cancer Research, Brussels B-1200, Belgium. Tel.: 32-2-764-7540; Fax: 32-2-764-6566; E-mail: stefan.constantinescu{at}bru.licr.org.

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