Klingmüller U, Bergelson S, Hsiao J G, Lodish H F
Whitehead Institute for Biomedical Research, Nine Cambridge Center, MA 02142, USA.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8324-8. doi: 10.1073/pnas.93.16.8324.
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 Y343 or Y401 is sufficient to mediate maximal activation of STAT5; tyrosine residues Y429 and Y431 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 EPO-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.
通过促红细胞生成素受体（EPO-R）进行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的同源二聚化，触发受体相关激酶JAK2的激活以及STAT5的激活。通过突变EPO-R胞质结构域中的八个酪氨酸残基，我们发现Y343或Y401足以介导STAT5的最大激活；酪氨酸残基Y429和Y431可部分激活STAT5。对这些酪氨酸周围序列的比较揭示YXXL是将STAT5招募到EPO-R的可能基序。在胞质结构域中缺乏所有八个酪氨酸残基的突变型EPO-R 的表达支持了低但可检测水平的EPO诱导的STAT5激活，表明存在独立于EPO-R中任何酪氨酸的STAT5激活替代途径。无论EPO-R中的哪个酪氨酸残基介导其激活或是否使用替代途径，STAT5激活和失活的动力学都是相同的。突变型EPO-R激活STAT5的能力与其促有丝分裂潜力没有直接相关性。
