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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5215-5222. Prepublished online as a Blood First Edition Paper on February 27, 2007; DOI 10.1182/blood-2006-10-055350. This Article Full Text (PDF) All Versions of this Article: blood-2006-10-055350v1 109/12/5215    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meyer, L. Articles by Verdier, F. Search for Related Content PubMed PubMed Citation Articles by Meyer, L. Articles by Verdier, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 30, 2006 Accepted February 14, 2007 Beta-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation Laure Meyer, Benedicte Deau, Hana Forejtnikova, Dominique Dumenil, Florence Margottin-Goguet, Catherine Lacombe, Patrick Mayeux*, and Frederique Verdier Departement d'Hematologie, Institut Cochin, Paris, France INSERM, U567, Paris, France CNRS, UMR8104, Paris, France Universite Paris Descartes, Faculte de Medecine Rene Descartes, Paris, France Departement des Maladies Infectieuses, Institut Cochin, Paris, France Laboratoire d'Hematologie, Assistance Publique-Hopitaux de Paris, Hopital Cochin, Paris, France * Corresponding author; email: mayeux{at}cochin.inserm.fr. Control of intensity and duration of erythropoietin (Epo) signalling is necessary to tightly regulate red blood cell production. We have recently shown that the ubiquitin/ proteasome system plays a major role in the control of Epo-R signalling. Indeed, after Epo stimulation the Epo-R is ubiquitinated and its intracellular part is degraded by the proteasome preventing further signal transduction. The remaining part of the receptor and associated Epo are internalised and degraded by the lysosomes (Walrafen et al. 2005, Blood 105,600-608). We show here that -Trcp is responsible for Epo-R ubiquitination and degradation. After Epo stimulation, -Trcp binds to the Epo-R. This binding, like Epo-R ubiquitination, requires Jak2 activation. The Epo-R contains a typical DSG binding sequence for -Trcp that is highly conserved among species. Interestingly, this sequence is located in a region of the Epo-R that is deleted in patients with familial polycythemia. Mutation of the serine residue of this motif to alanine (Epo-RS462A) abolished -Trcp binding, Epo-R ubiquitination and degradation. Epo-RS462A activation was prolonged and BaF3 cells expressing this receptor are hypersensitive to Epo, suggesting that part of the hypersensitivity to Epo in familial polycythemia could be due to the lack of -Trcp recruitment to the Epo-R. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Jia, R. Warin, X. Yu, R. Epstein, and C. T. Noguchi Erythropoietin signaling promotes transplanted progenitor cell survival FASEB J, September 1, 2009; 23(9): 3089 - 3099. [Abstract] [Full Text] [PDF] R. Sulahian, O. Cleaver, and L. J.-s. Huang Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia Blood, May 21, 2009; 113(21): 5287 - 5297. [Abstract] [Full Text] [PDF] T. M. Piazza, J.-C. Lu, K. C. Carver, and L. A. Schuler Src Family Kinases Accelerate Prolactin Receptor Internalization, Modulating Trafficking and Signaling in Breast Cancer Cells Mol. Endocrinol., February 1, 2009; 23(2): 202 - 212. [Abstract] [Full Text] [PDF] B. Varghese, H. Barriere, C. J. Carbone, A. Banerjee, G. Swaminathan, A. Plotnikov, P. Xu, J. Peng, V. Goffin, G. L. Lukacs, et al. Polyubiquitination of Prolactin Receptor Stimulates Its Internalization, Postinternalization Sorting, and Degradation via the Lysosomal Pathway Mol. Cell. Biol., September 1, 2008; 28(17): 5275 - 5287. [Abstract] [Full Text] [PDF] J. Fang, M. Menon, D. Zhang, B. Torbett, L. Oxburgh, M. Tschan, E. Houde, and D. M. Wojchowski Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2 Blood, August 1, 2008; 112(3): 886 - 890. [Abstract] [Full Text] [PDF] F. Mannello and G. A. M. Tonti Erythropoietin and Its Receptor in Breast Cancer: Putting Together the Pieces of the Puzzle Oncologist, July 1, 2008; 13(7): 761 - 768. [Abstract] [Full Text] [PDF] G. Swaminathan, B. Varghese, C. Thangavel, C. J Carbone, A. Plotnikov, K G S. Kumar, E. M Jablonski, C. V Clevenger, V. Goffin, L. Deng, et al. Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2 J. Endocrinol., February 1, 2008; 196(2): R1 - R7. [Abstract] [Full Text] [PDF]

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