Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors
Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors
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DOI：
10.1073/pnas.94.7.3016
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发表时间：
1997-04-01
影响因子：
11.1
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Klingmuller, U;Wu, H;Lodish, HF
促红细胞生成素（EPO）受体（EPO-R）响应EPO结合的同源二聚化瞬时激活受体相关蛋白酪氨酸激酶JAK 2。EPO-R的酪氨酸磷酸化为信号分子如蛋白酪氨酸磷酸酶SH-PTP 1和SH-PTP 2、磷酸肌醇3-激酶（PI 3激酶）和STAT 5中的SH 2结构域创建“停靠位点”。然而，对红系祖细胞增殖和分化所必需的特异性细胞内信号知之甚少。在这里，我们表明，EPO-R仅含有一个胞质（磷酸）酪氨酸残基，Y 479，诱导信号转导途径足以增殖和分化的胎肝祖细胞的红系集落形成单位从EPO-R（-/-）小鼠，以及增殖培养的造血细胞，该级联反应涉及EPO诱导的PI 3激酶向EPO-R的连续募集和促分裂原活化蛋白激酶活性的活化，独立于Shc/Grb 2-衔接子途径和STAT 5。蛋白激酶C β可能是连接PI 3激酶与丝裂原活化蛋白激酶信号级联的介质之一。我们的研究结果确定了一个重要的信号级联在体内红系细胞增殖和分化。
Homodimerization of the erythropoietin (EPO) receptor (EPO-R) in response to EPO binding transiently activates the receptor-associated protein tyrosine kinase JAK2. Tyrosine phosphorylation of the EPO-R creates ''docking sites'' for SH2 domain(s) in signaling molecules such as the protein tyrosine phosphatases SH-PTP1 and SH-PTP2, phosphoinositide 3-kinase (PI3 kinase), and STAT5. However, little Is known about the specific intracellular signals essential for proliferation and differentiation of erythroid progenitors. Here we show that an EPO-R containing only one cytosolic (phospho)tyrosine residue, Y479, induces a signal transduction pathway sufficient for proliferation and differentiation of fetal liver progenitors of erythroid colony-forming units from EPO-R(-/-) mice as well as for proliferation of cultured hematopoietic cells, This cascade involves sequential EPO-induced recruitment of PI3 kinase to the EPO-R and activation of mitogen-activated protein kinase activity, independent of the Shc/Grb2-adapter pathway and of STAT5. Protein kinase C epsilon may be one of the mediators connecting PI3 kinase with the mitogen-activated protein kinase signaling cascade. Our results identify a signaling cascade important in vivo for erythroid cell proliferation and differentiation.