Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5
Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5
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DOI：
10.1073/pnas.93.16.8324
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发表时间：
1996-08-06
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;Bergelson, S;Lodish, HF
通过促红细胞生成素受体 (EPO-R) 的信号传导对于红系祖细胞的增殖、分化和存活至关重要，EPO 诱导 EPO-R 的同二聚化，触发受体相关激酶 JAK2 的激活和 STAT5 的激活。通过突变 EPO-R 胞质结构域中的 8 个酪氨酸残基，我们表明 Y-343 或 Y-401 足以介导 STAT5 的最大激活：酪氨酸残基 Y-429 和 Y-431 可以部分激活 STAT5。对这些酪氨酸周围的序列进行比较表明，YXXL 可能是指定将 STAT5 募集到 EPO-R 的基序。胞浆结构域中缺乏全部八个酪氨酸残基的突变 EPO-R 的表达支持较低但可检测水平的 EPO 诱导的 STAT5 激活，表明存在独立于 EPO-R 中任何酪氨酸的 STAT5 激活的替代途径。 STAT5激活和失活的动力学是相同的，无论Ii;PO-R中的哪个酪氨酸残基介导其激活或是否使用旁路途径，突变型EPO-R激活STAT5的能力与其促有丝分裂潜力不直接相关。
Signaling through the erythropoietin receptor (EPO-R) is crucial for proliferation, differentiation, and survival of erythroid progenitor cells, EPO induces homodimerization of the EPO-R, triggering activation of the receptor-associated kinase JAK2 and activation of STAT5. By mutating the eight tyrosine residues in the cytosolic domain of the EPO-R, we show that either Y-343 or Y-401 is sufficient to mediate maximal activation of STAT5: tyrosine residues Y-429 and Y-431 can partially activate STAT5. Comparison of the sequences surrounding these tyrosines reveals YXXL as the probable motif specifying recruitment of STAT5 to the EPO-R. Expression of a mutant EPO-R lacking all eight tyrosine residues in the cytosolic domain supported a low but detectable level of EPO-induced STAT5 activation, indicating the existence of an alternative pathway for STAT5 activation independent of any tyrosine in the EPO-R. The kinetics of STAT5 activation and inactivation were the same, regardless of which tyrosine residue in the Ii;PO-R mediated its activation or whether the alternative pathway was used, The ability of mutant EPO-Rs to activate STAT5 did not directly correlate with their mitogenic potential.