title: Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2.
abstract: 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.
authors.affiliation: Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Marc A
authors.initials: MA
authors.lastname: Kerenyi
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Verena
authors.initials: V
authors.lastname: Becker
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: Ernst W
authors.initials: EW
authors.lastname: Müllner
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
mesh_terms: 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*
chemical_list: D016207:Cytokines; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D053614:Janus Kinase 2