Biology Reference
In-Depth Information
“P” stain, encode two types of gp55 (gp55-A and gp55-P, respectively). Both
bind to and abnormally activate murine, but not human, EPOR [30, 31].
gp55-P is more potent than gp55-A in activating EPOR and leads to EPO-inde-
pendent proliferation of host cells [32]. The interaction of gp55 and EPOR is
through their transmembrane domains [33, 34]. Mutagenesis studies of both
murine and human EPOR transmembrane domains identified that Ser238 in
murine EPOR is critical for EPOR-specific interaction with gp55 [35]. In addi-
tion, computational modeling and mutagenesis studies showed that gp55-P
Met390, which interacts with Ser238 of EPOR, is the key amino acid in the
transmembrane domain essential for the full function of gp55-P [35]. gp55-P
and gp55-A are thought to activate EPOR signaling by inducing receptor
oligomerization, which constitutively activates downstream Raf-1/MAPK and
PI-3/Akt pathways [36, 37].
Kinases interacting with EPOR
JAK-2 signaling
Activation of the cytoplasmic tyrosine kinase JAK-2 appears to be the initiat-
ing event of EPOR signal transduction [38]. Activated JAK-2 phosphorylates
various substrates, including multiple tyrosine residues on EPOR. These phos-
phorylated tyrosines serve as docking sites for SH2 domain-containing pro-
teins. Binding of SH2-containing proteins to EPOR phosphotyrosines activates
signaling by the signal transducer and activators of transcription STAT5, phos-
pholipid modifying enzymes (PI-3-Kinase, PLC-
, and SHIP), regulators of
γ
γ
Ras and MAP kinase signaling, tyrosine phosphatases (SHP1 and SHP2), sup-
pressors of cytokine signaling (CIS and SOCS3), and Src-family kinases [38].
Constitutive activation of human JAK-2, caused by either overexpression or
chromosomal translocation, results in leukemias, e.g., acute lymphoblastic
leukemia or chronic myelogenous leukemia [39-41]. Consistently, a mutation
in the JAK homolog in
Drosophila
,hopscotch, causes abnormal proliferation
and differentiation of the larval hematopoietic system and leads to lethality
[42].
In addition to the hematopoietic system, EPOR signaling through JAK-2 is
important in neural progenitor cell survival and neuronal protection in models
of ischemic and degenerative damage [4, 5].
JAK-2 knockouts
The physiological importance of JAK-2 in EPOR signaling is best demon-
strated through JAK-2-deficient mice. JAK-2 knockout mice die about E12.5
of embryogenesis due to severe anemia, a phenotype similar to, but more
severe than, EPOR knockout mice [43, 44]. Analysis of JAK-2
-/-
fetal liver
cells in culture demonstrated that myeloid progenitors are decreased in num-
ber in these mice and they fail to respond to a variety of cytokines and growth
factors including EPO.
