beta-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation.
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 beta-Trcp is responsible for Epo-R ubiquitination and degradation. After Epo stimulation, beta-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 beta-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 beta-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 beta-Trcp recruitment to the Epo-R.
Meyer
Laure
L
Institut Cochin, Département d'Hématologie, Paris, France.
Deau
Bénédicte
B
Forejtníková
Hana
H
Duménil
Dominique
D
Margottin-Goguet
Florence
F
Lacombe
Catherine
C
Mayeux
Patrick
P
Verdier
Frédérique
F
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D004705:Endocytosis; D006801:Humans; D051379:Mice; D011485:Protein Binding; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology*
D017467:Receptors, Erythropoietin; D014452:Ubiquitins; D044844:beta-Transducin Repeat-Containing Proteins