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J. Biol. Chem., Vol. 275, Issue 24, 18375-18381, June 16, 2000
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From the The binding of erythropoietin (Epo) to its
receptor leads to the transient phosphorylation of the Epo receptor
(EpoR) and the activation of intracellular signaling pathways.
Inactivation mechanisms are simultaneously turned on, and Epo-induced
signaling pathways return to nearly basal levels after 30-60 min of
stimulation. We show that proteasomes control these inactivation
mechanisms. In cells treated with the proteasome inhibitors
N-Ac-Leu-Leu-norleucinal (LLnL) or lactacystin, EpoR
tyrosine phosphorylation and activation of intracellular signaling
pathways (Jak2, STAT5, phosphatidylinositol 3-kinase) were sustained
for at least 2 h. We show that this effect was due to the
continuous replenishment of the cell surface pool of EpoRs in cells
treated with proteasome inhibitors. Proteasome inhibitors did not
modify the internalization and degradation of Epo·EpoR complexes, but
they allowed the continuous replacement of the internalized receptors
by newly synthesized receptors. Proteasome inhibitors did not modify
the synthesis of EpoRs, but they allowed their transport to the cell
surface. N-Ac-Leu-Leu-norleucinal, but not lactacystin,
also inhibited the degradation of internalized Epo·EpoR complexes,
most probably through cathepsin inhibition. The internalized EpoRs were
not tyrosine-phosphorylated, and they did not activate intracellular
signaling pathways. Our results show that the proteasome controls the
down-regulation of EpoRs in Epo-stimulated cells by inhibiting the cell
surface replacement of internalized EpoRs.
Proteasomes Regulate the Duration of Erythropoietin Receptor
Activation by Controlling Down-regulation of Cell Surface
Receptors*
§,,,,
, and**
Institut Cochin de Génétique
Moléculaire, INSERM U363 and the Service
d'Hématologie, Hôpital Cochin, Université René
Descartes, 27 Rue du Faubourg Saint Jacques, F75014 Paris, and the
¶ Institut National de la Transfusion Sanguine, 6 Rue Alexandre
Cabanel, F75015 Paris, France
*
This work was supported in part by a grant from the
Comité de Paris of the Ligue Nationale Contre le Cancer
(Associate Laboratory 8).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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