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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.


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HEMATOPOIESIS

ß-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation

Laure Meyer1,3,5, Bénédicte Deau1,3,5, Hana Forejtníková1,3,5, Dominique Duménil1,3,5, Florence Margottin-Goguet2,5, Catherine Lacombe1,3,5, Patrick Mayeux1,3,5, and Frédérique Verdier1,3,5

1 Institut Cochin, Département d'Hématologie, Paris, France; 2 Institut Cochin, Département des Maladies Infectieuses, Paris, France; 3 Institut National de la Santé et de la Recherche, Médicale (INSERM), U567, Paris, France; 4 Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; 5 Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S 8104, Paris, France; 6 Laboratoire d'Hématologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

Control of intensity and duration of erythropoietin (Epo) signaling 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 signaling. Indeed, after Epo stimulation, 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 internalized and degraded by the lysosomes. We show that ß-Trcp is responsible for Epo-R ubiquitination and degradation. After Epo stimulation, ß-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 ß-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 ß-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 the result of the lack of ß-Trcp recruitment to the Epo-R.


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