Ghaffari S, Kitidis C, Fleming M D, Neubauer H, Pfeffer K, Lodish H F
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Blood. 2001 Nov 15;98(10):2948-57. doi: 10.1182/blood.v98.10.2948.
The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2(-/-) embryos are severely deficient in erythropoiesis and die at an early stage of development from fetal anemia. The binding of erythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosphorylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study explored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and primary erythroid cells expressing BCR-ABL. However, BCR-ABL effectively supports normal erythroid proliferation, differentiation, and maturation in JAK2-deficient fetal liver cells. Using mutants of BCR-ABL, this study shows that certain signaling pathways activated by BCR-ABL segments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2(-/-) progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed.
受体相关蛋白酪氨酸激酶janus激酶2（JAK2）对于正常红细胞发育和促红细胞生成素受体（EpoR）信号传导至关重要。JAK2基因敲除（-/-）胚胎的红细胞生成严重不足，并因胎儿贫血在发育早期死亡。促红细胞生成素（Epo）与EpoR的结合会触发JAK2的激活、EpoR的磷酸化以及EpoR信号级联反应的启动。除了Epo与其受体结合外，EpoR下游的信号通路也可被BCR-ABL癌蛋白激活。本研究探讨了JAK2是否是BCR-ABL介导的红细胞生成刺激所必需的。在此研究中发现，在表达BCR-ABL的培养细胞和原代红系细胞中，JAK2持续发生酪氨酸磷酸化。然而，BCR-ABL能有效支持JAK2缺陷型胎儿肝细胞的正常红系增殖、分化和成熟。利用BCR-ABL突变体，本研究表明，由BCR-ABL中与其酪氨酸激酶结构域不同的片段激活的某些信号通路，对于挽救JAK2基因敲除（-/-）祖细胞中的红细胞生成至关重要。文中还讨论了这些多种信号通路对正常红系发育的影响。
