Biology Reference
In-Depth Information
kinase activity
in vitro
[126]. SOCS-3 is highly expressed in the erythroid lin-
eage during embryonic development, and deletion of SOCS-3 results in
embryonic lethality at E12 to E16 associated with erythrocytosis [127]. These
studies identify SOCS-3 as a major negative regulator of fetal liver erythro-
poiesis possibly through negative regulation of EPOR/JAK-2 signaling. The
exact mechanism of negative regulation of EPOR signaling by SOCS-3
requires additional investigation.
Phosphatases
Three phosphatases interact with EPOR, including SH2-containing protein
tyrosine phosphatase 1 (SH-PTP1 or SHP1), SHP2, and SH2-containing inos-
itol-5-phosphatase (SHIP) [128]. Among them, only SHP1 is a negative regu-
lator of the phosphorylated EPOR. SHP1 binds to the (P)Y429 of EPOR after
EPO addition [129]. Cells expressing EPOR Y429F mutant are hypersensitive
to EPO and show a prolonged EPO-induced autophosphorylation of JAK-2,
suggesting that SHP1 dephosphorylates and inactivates JAK-2 [129, 130].
Furthermore, mice with the deletion of EPOR distal region (including Y429)
display erythrocytosis when challenged with continuous EPO injections [52].
In
motheaten
mice, which carry a spontaneously occurring SHP1 mutation,
many hematopoietic cell lineages show hyperproliferation, including splenic
CFU-E [131-133]. This phenotype is reminiscent of familial polycythemia
observed in human patients carrying mutated EPOR. To date, among the ten
published EPOR mutations associated with erythrocytosis, six have
C
-termi-
nal truncations missing Y429, supporting the negative regulatory role of the
EPOR Y429 and its associated SHP1 [134-144]. In contrast, SHP2 and SHIP
act as positive effectors in erythropoiesis. In embryonic stem cells carrying a
SHP2 mutant with a disrupted
N
-terminal SH2 domain, the production of ery-
N
throid cells in embryoid bodies is suppressed [145, 146]. Similarly, in SHIP
-/-
mice, the number of bone marrow-derived CFU-E is decreased [147].
CD45 is another phosphatase with a potential role in EPOR signaling.
CD45 is a transmembrane phosphatase that is highly expressed on hematopoi-
etic cells and has been shown as a key regulator of antigen receptor signaling
in T and B cells [148, 149]. Targeted disruption of CD45 leads to enhanced
activation of JAK-2 signaling [150].
In vitro
studies showed that CD45 could
directly dephosphorylate JAK-2 and negatively regulate EPOR signaling
[150]. CD45 is present only on a small, relatively immature subset of EPOR-
expressing erythroid cells in the bone marrow [151, 152]. In particular, CD45
is not expressed on CFU-E or erythroblasts, suggesting that the potential phys-
iological role of CD45 in the regulation of EPOR signaling occurs in
pre-CFU-E erythroid progenitor cell.
