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Erythropoietin receptors on murine erythroid colony-forming units: natural
history
KT Landschulz, AN Noyes, O Rogers and SH Boyer
Department of Medicine, Johns Hopkins University School of Medicine and
Hospital, Baltimore, MD 21205.
Erythropoietin (Epo) response and binding was assessed in purified murine
CFU-E and their descendants. Several features emerged. First, Epo on CFU-E
is in rapid flux: Half-time for 125I-Epo internalization is approximately
four to five minutes. Second, computer-aided Scatchard analyses indicate
that greater than 70 high-affinity Epo-receptor sites on anemic animal
CFU-E are sometimes already occupied by Epo acquired in vivo. When this is
removed, 40% of greater than or equal to 370 sites per CFU-E belong to a
high-affinity class (dissociation constant, kd: 73 pmol/L +/- 15 [SE]) and
60% belong to a low-affinity class (kd: 813 pmol/L +/- 246). Third, the few
small colonies that develop from CFU-E in the absence of Epo are shown, by
serial assay of 59Fe-heme biosynthesis, to stem from contaminating
erythroblasts: a result consistent with our finding that, after eight-hour
CFU-E culture, most erythroblasts no longer require appreciable Epo for
growth. Thus, although the early need for Epo by CFU-E is nearly absolute,
this need is not met by the often substantial Epo already on board. The
inference is that repeated occupancy of the rapidly turning over Epo
receptors is required. Fourth, Epo bound and/or internalized by CFU-E
descendants decreases to 40% of zero-time levels after 14 hours in
Epo-supplemented culture and disappears after 28 hours. Scatchard analyses
indicate that 73 pmol/L kd receptor sites become undetectable at seven to
eight hours, whereas 813 pmol/L kd sites are undiminished and only
one-third less by 16 hours. This apparent disappearance of high-affinity
sites and persistence of low-affinity sites suggests that (a) at least two
gene products mediate Epo binding, eg, two different receptor polypeptides
or one receptor and one cofactor which modulates affinity; (b)
high-affinity sites mediate the growth function of Epo during the first
eight hours of culture; and (c) lingering low-affinity receptors may
mediate some unrecognized Epo function. Fifth, the efficiency with which
106- and 91-Kd CFU-E membrane polypeptides can be cross-linked to 125I-Epo
is two- to threefold higher for cells labeled at high Epo concentrations
than at low ones, which suggests that these polypeptides largely reflect
low-affinity site reactions.
Volume 73,
Issue 6,
pp. 1476-1486,
05/01/1989
Copyright © 1989 by The American Society of Hematology
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