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Blood, 15 January 2005, Vol. 105, No. 2, pp. 600-608.
Prepublished online as a Blood First Edition Paper on September 9, 2004; DOI 10.1182/blood-2004-03-1216.
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HEMATOPOIESIS
Both proteasomes and lysosomes degrade the activated erythropoietin receptor
Pierre Walrafen,
Frédérique Verdier,
Zahra Kadri,
Stany Chrétien,
Catherine Lacombe, and
Patrick Mayeux
From the Département d'Hématologie, Institut Cochin, Institut National de la Santéet de la Recherche Médicale U567 (Paris, France), Centre National de la Recherche Scientifique UMR 8104, Université René Descartes; and Laboratoire d'Hématologie, Assistance Publique—Hôpitaux de Paris, Hôpital Cochin, Paris, France.
Activation of the erythropoietin receptor (EpoR) after Epo binding is very transient because of the rapid activation of strong down-regulation mechanisms that quickly decrease Epo sensitivity of the cells. Among these down-regulation mechanisms, receptor internalization and degradation are probably the most efficient. Here, we show that the Epo receptor was rapidly ubiquitinated after ligand stimulation and that the C-terminal part of the Epo receptor was degraded by the proteasomes. Both ubiquitination and receptor degradation by the proteasomes occurred at the cell surface and required Janus kinase 2 (Jak2) activation. Moreover, Epo-EpoR complexes were rapidly internalized and targeted to the lysosomes for degradation. Neither Jak2 nor proteasome activities were required for internalization. In contrast, Jak2 activation was necessary for lysosome targeting of the Epo-EpoR complexes. Blocking Jak2 with the tyrphostin AG490 led to some recycling of internalized Epo-Epo receptor complexes to the cell surface. Thus, activated Epo receptors appear to be quickly degraded after ubiquitination by 2 proteolytic systems that proceed successively: the proteasomes remove part of the intracellular domain at the cell surface, and the lysosomes degrade the remaining part of the receptor-hormone complex. The efficiency of these processes probably explains the short duration of intracellular signaling activated by Epo.
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