Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2.
Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine- and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropoiesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling.
Grebien
Florian
F
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria.
Kerenyi
Marc A
MA
Kovacic
Boris
B
Kolbe
Thomas
T
Becker
Verena
V
Dolznig
Helmut
H
Pfeffer
Klaus
K
Klingmüller
Ursula
U
Müller
Mathias
M
Beug
Hartmut
H
Müllner
Ernst W
EW
Moriggl
Richard
R
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004920:Erythropoiesis; D053614:Janus Kinase 2; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor / Q000378:metabolism*
D016207:Cytokines; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D053614:Janus Kinase 2