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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2667-2675
Activation of the Erythropoietin Receptor Is Not Required for
Internalization of Bound Erythropoietin
Diana L. Beckman,
Lilie L. Lin,
Mary E. Quinones, and
Gregory D. Longmore
From the Departments of Medicine and Cell Biology, Washington
University School of Medicine, St Louis, MO.
Erythropoietin (EPO) is required for the survival and expansion of
red blood cell progenitor cells and supports continued differentiation
of these committed progenitors to mature red blood cells. After binding
to its cognate receptor, EPO promotes receptor homodimerization,
activation of receptor-associated JAK2, subsequent receptor tyrosine
phosphorylation, and transduction of signal. EPO is also internalized
and degraded in lysosomes. The contribution of EPO-induced receptor
internalization to modulation of EPO signals has not been determined.
To examine this question, we generated a panel of hematopoietic cell
lines containing progressively truncated isoforms of the erythropoietin
receptor (EPO-R) and determined the rate and extent of EPO
internalization and receptor downregulation. We demonstrated that a
membrane-proximal domain of the cytoplasmic tail of the EPO-R was the
minimal region required for EPO-induced receptor internalization. This
cytoplasmic domain is also the minimal domain required for activation
of JAK2, a cytosolic tyrosine kinase essential for the function of the
EPO-R. However, neither EPO activation of cytosolic JAK2 tyrosine
kinase activity nor tyrosine phosphorylation of the EPO-R cytoplasmic
tail was required for EPO-induced receptor downregulation. Both
functional and nonfunctional cell surface receptor isoforms were
internalized equally. These results suggest that, for downregulation of
cell surface ligand occupied EPO-R and possibly for signaling receptors
of the cytokine receptor superfamily in general, internalization of
cell surface ligand occupied receptors may follow a pathway distinct
from signaling receptors of the receptor tyrosine kinase (RTK) family.
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