Biology Reference
In-Depth Information
Figure 3. Regulation of the erythropoietic response. ON = EPO engagement of its receptor with trans-
f
mission of signal through JAK2 and STAT/5 and amplification by PI3-K and Ras. OFF = absence of
EPO; negative regulators of the EPO receptor (EPOR) including SHP-1 phosphatase.
Apoptosis = Fas/FasL activation of death pathway. Presence or absence of GATA-1 and Bcl-X
L
activ-
ity is indicated in each segment. (Israels LG and Israels ED, 2000. Used with permission of Core
Health Services Inc.)
e
Primary familial erythrocytosis is an autosomal-dominant disease due to a
mutated EPOR gene, the result of missense or frame shift mutations that affect
the binding site for SHP-1. The abnormal cytoplasmic tail of the receptor is
either truncated or is insensitive to the SHP-1 phosphatase that normally turns
off the EPO signal [38, 39]. The mutated receptor is hyper-responsive to the
EPO ligand and, as a result, the proliferative response is maintained in the
presence of a minimal EPO stimulus. Patients are reported to have early car-
diovascular disease (although one propositus of a Finnish family won three
Olympic gold medals in cross-country skiing, possibly the advantage of an
