Biology Reference
In-Depth Information
Knock-outs
STAT5A and B are 96% identical in amino acid composition, and form
homodimers or heterodimers upon phosphorylation. STAT5A- and STAT5B-
deficient mice show distinct phenotypes and reveal important functions for
these proteins in prolactin and GH signaling, respectively [80, 81]. Alterations
in hematopoiesis of STAT5A
-/-
or STAT5B
-/-
mice have not been reported.
Deletion of both STAT5A and STAT5B in mice [82] results in anemia during
embryogenesis and marked increase in apoptosis of erythroid cells [74]. In
addition, some adult STAT5A
-/-
/STAT5B
- -/-
mice have near-normal hematocrit
but are deficient in induction of erythropoiesis during stress-induced anemia
[83]. In these mice, erythropoiesis is blocked at early erythroblasts that under-
go apoptosis and fail to mature to late erythroblasts.
PI3-kinase/AKT
Activation of PI3-kinase and downstream AKT pathways
PI3-kinase signaling is activated in response to EPO stimulation in several
EPO-dependent cultured cells. EPOR Y479 is essential for binding to the P85
sub-unit of PI3-kinase that activates PI3-kinase in response to EPO [84-86].
In particular, EPO stimulation of the F7Y479 EPOR mutant, in which all
cytosolic tyrosines but Y479 are mutated to phenylalanine, activates PI3-
Kinase and ERK but not STAT5. (P) Y479 recruits PI3-kinase to EPOR,
resulting in RAS-independent activation of a MAPK cascade (ERK1/2) [86].
A role for protein kinase C as an intermediate has also been suggested
[86-88]. It is not clear whether (P) Y479 also supports the activation of other
MAPK pathways (JNK, p38). Each of two tyrosines, Y464 and Y479, alone
can mediate a proliferative signal in Baf3 cells. Y479 but not Y464 is also
capable of inducing the differentiation of over 85% of CFU-E. (P) Y479 is the
only tyrosine residue on EPOR that can support both proliferation and differ-
entiation of erythroid cells to the same extent as the wild-type receptor [68],
suggesting that pathways additional to ERK may also be activated by PI3-
kinase in response to EPO. Both PI3-kinase/AKT and MAPK pathways
appear to be required for EPO-independent leukemic transformation of
proerythroblasts [88, 89]. Inhibition of PI3-kinase activation prevents differ-
entiation of primary human erythroid progenitor cells in culture, suggesting an
important role for PI3-kinase activation in generation of erythroid cells [90,
91]. Less is known about the contribution of PI3-kinase activation to erythroid
cell formation
in vivo.
It has been proposed more recently that additional pathways activated by
EPO and distinct from (P) Y479, may result in PI3-kinase activation. For
instance, in the primitive hematopoietic UT7 cells, EPOR is constitutively
associated with insulin receptor substrate (IRS)-2. After EPO stimulation,
IRS-2 is rapidly tyrosine phosphorylated and associates with the P85 sub-unit
of PI3-kinase and with phosphatidylinositol 3,4,5 triphosphate 5-phosphatase
