Maturation of erythroid cells and erythroleukemia development are affected by the kinase activity of Lyn.
Maturation of erythroid cells and erythroleukemia development are affected by the kinase activity of Lyn.
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红系细胞的成熟和红白血病的发展受到 Lyn 激酶活性的影响。
作者：
P. A. Tilbrook;Gene A. Palmer;T. Bittorf;D. J. McCarthy;Michael J Wright;M. Sarna;D. Linnekin;V. Cull;James H. Williams;E. Ingley;Jens Schneider;Gerald Krystal;S. Klinken
本研究探讨酪氨酸激酶Lyn对促红细胞生成素诱导的红细胞胞内信号传导的影响。在J2E红白血病细胞中，Lyn与多种蛋白共免疫沉淀，包括SHP-1、SHP-2、ras- gtpase激活蛋白、信号转导和转录激活因子（STAT） 5a、STAT5b和丝裂原激活蛋白激酶；然而，引入显性阴性Lyn （Y397F Lyn）抑制了Lyn与除SHP-1外的所有这些分子的相互作用。含有显性阴性Lyn的细胞显示出细胞内磷酸化模式的改变，包括丝裂原活化蛋白激酶，但不包括促红细胞生成素受体、janus活化激酶（JAK） 2或STAT5。结果，促红细胞生成素诱导的分化和基础增殖严重受损。Y397F Lyn使红系转录因子红系kruppel样因子和GATA-1蛋白水平降低高达90%，这是表达Y397F Lyn的J2E细胞无法合成血红蛋白的原因。虽然Lyn被证明可以结合红细胞生成素受体细胞质域的几个位点，但当JAK2结合位点突变的受体在J2E细胞中异位表达时，它没有被激活，这表明JAK2是促红细胞生成素信号传导的初级激酶，而Lyn是次级激酶。在正常红细胞祖细胞中，促红细胞生成素增强Lyn的磷酸化；此外，外源Lyn增加了来自正常祖细胞的单位红系集落形成，但没有爆裂形成单一红系集落，表明该激酶具有阶段特异性作用。值得注意的是，改变J2E细胞中的Lyn活性对体内红白血病的发展有深远的影响：当将野生型Lyn或Y397F Lyn引入这些细胞时，死亡率显著降低，潜伏期延长。综上所述，这些数据表明Lyn在非转化红细胞和白血病红细胞的细胞内信号传导中起重要作用。
This study examined the impact of the tyrosine kinase Lyn on erythropoietin-induced intracellular signaling in erythroid cells. In J2E erythroleukemic cells, Lyn coimmunoprecipitated with numerous proteins, including SHP-1, SHP-2, ras-GTPase-activating protein, signal transducers and activators of transcription (STAT) 5a, STAT5b, and mitogen-activated protein kinase; however, introduction of a dominant-negative Lyn (Y397F Lyn) inhibited the interaction of Lyn with all of these molecules except SHP-1. Cells containing the dominant-negative Lyn displayed altered intracellular phosphorylation patterns, including mitogen-actiated protein kinase, but not erythropoietin receptor, Janus-activated kinase (JAK) 2, or STAT5. As a consequence, erythropoietin-initiated differentiation and basal proliferation were severely impaired. Y397F Lyn reduced the protein levels of erythroid transcription factors erythroid Kruppel-like factor and GATA-1 up to 90%, which accounts for the inability of J2E cells expressing Y397F Lyn to synthesize hemoglobin. Although Lyn was shown to bind several sites on the cytoplasmic domain of the erythropoietin receptor, it was not activated when a receptor mutated at the JAK2 binding site was ectopically expressed in J2E cells indicating that JAK2 is the primary kinase in erythropoietin signaling and that Lyn is a secondary kinase. In normal erythroid progenitors, erythropoietin enhanced phosphorylation of Lyn; moreover, exogenous Lyn increased colony forming unit-erythroid, but not burst forming uniterythroid, colonies from normal progenitors, demonstrating a stage-specific effect of the kinase. Significantly, altering Lyn activity in J2E cells had a profound effect on the development of erythroleukemias in vivo: the mortality rate was markedly reduced and latent period extended when either wild-type Lyn or Y397F Lyn was introduced into these cells. Taken together, these data show that Lyn plays an important role in intracellular signaling in nontransformed and leukemic erythroid cells.
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DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Cichowski,K;McCormick,F;Brugge,JS
通讯作者：
Brugge,JS
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影响因子：
20.3
作者：
Youssoufian,H;Longmore,G;Neumann,D;Yoshimura,A;Lodish,HF
通讯作者：
Lodish,HF
Friend脾病灶形成病毒糖蛋白gp55与内质网中的促红细胞生成素受体相互作用并影响受体代谢。
DOI：
10.1073/pnas.87.11.4139
发表时间：
1990
影响因子：
11.1
作者：
Yoshimura,A;D'Andrea,AD;Lodish,HF
通讯作者：
Lodish,HF
鸡红细胞祖细胞和癌基因转化的成红细胞的酪氨酸激酶表达谱。
影响因子：
11
作者：
Robinson,D;Chen,HC;Li,D;Yustein,JT;He,F;Lin,WC;Hayman,MJ;Kung,HJ
通讯作者：
Kung,HJ
对促红细胞生成素没有反应的突变型 J2E 红系细胞系的进化。
影响因子：
11.4
作者：
Klinken,SP;Nicola,NA
通讯作者：
Nicola,NA