Grebien Florian, Kerenyi Marc A, Kovacic Boris, Kolbe Thomas, Becker Verena, Dolznig Helmut, Pfeffer Klaus, Klingmüller Ursula, Müller Mathias, Beug Hartmut, Müllner Ernst W, Moriggl Richard
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria.
Blood. 2008 May 1;111(9):4511-22. doi: 10.1182/blood-2007-07-102848. Epub 2008 Jan 31.
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.
红细胞生成需要促红细胞生成素（Epo）和干细胞因子（SCF）通过其受体EpoR和c-Kit进行信号传导。与许多参与造血的其他受体一样，EpoR通过激酶Jak2发挥作用。EpoR或Janus激酶2（Jak2）的缺失会因红细胞生成缺陷而导致胚胎致死。不同的EpoR/Jak2诱导的信号通路（丝裂原活化蛋白激酶、磷脂酰肌醇3激酶、信号转导和转录激活因子5 [Stat5]）对功能性红细胞生成的贡献尚未完全了解。在这里，我们证明组成型激活的Stat5a突变体（cS5）的表达足以以不依赖Epo的方式缓解Jak2（-/-）和EpoR（-/-）细胞的增殖缺陷。此外，他莫昔芬诱导的Stat5a-雌激素受体（ER）*融合构建体的DNA结合能够在没有Epo的情况下实现红细胞生成。此外，c-Kit能够增强通过Jak2-Stat5轴的信号传导，特别是在淋巴样和髓样祖细胞中。尽管Jak2（-/-）胎肝中的造血干细胞数量减少了2.5倍，但将Jak2（-/-）-cS5胎肝细胞移植到受辐照小鼠体内后，在移植后长达6个月内产生了供体来源的成熟红细胞和髓细胞。细胞因子和c-Kit通路在造血过程中并非相互独立发挥作用，而是协同作用以实现Jak2/Stat5的完全激活。总之，激活的Stat5是Jak2在红细胞生成/髓细胞生成中的关键下游效应器，并且Jak2在功能上连接细胞因子与c-Kit受体酪氨酸激酶信号传导。
