Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD
Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD
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DOI：
10.1182/blood-2005-11-011429
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发表时间：
2006-08-15
期刊：
影响因子：
20.3
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
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作者：
Rocnik, Jennifer L.;Okabe, Rachel;Gilliland, D. Gary
FLT 3受体酪氨酸激酶的获得性突变在急性髓性白血病中很常见，并导致组成性激活。最常见的激活机制是通过内部串联重复（ITD）破坏质膜自动调节结构域。FLT 3-ITD在小鼠骨髓移植模型中赋予造血细胞因子非依赖性生长并诱导骨髓增殖综合征。我们和其他人已经观察到FLT 3-ITD激活STAT 5及其下游效应子，而配体刺激的野生型FLT 3（FLT 3 WT）则没有。在FLT 3-ITD中酪氨酸磷酸化位点的体外定位中，在luxtamembrane结构域内鉴定出2个被ITD破坏的候选STAT 5对接位点。在FLT 3-ITD的背景下，残基589和591的酪氨酸至苯丙氨酸取代不影响酪氨酸激酶活性，但消除了STAT 5活化。此外，FLT 3-ITD-Y 589/591 F在转导入原代鼠骨髓细胞时不能诱导骨髓增殖表型，而FLT 3-ITD诱导骨髓增殖性疾病，中位潜伏期为50天。因此，由ITD诱导的FLT 3跨膜结构域的构象变化通过自身抑制的失调激活激酶，并导致通过STAT 5的信号转导的定性差异，这对于FLT 3-ITD在体内的转化潜力是必需的。
Acquired mutations in the FLT3 receptor tyrosine kinase are common in acute myelold leukemia and result in constitutive activation. The most frequent mechanism of activation is disruption of the juxtamembrane autoregulatory domain by internal tandem duplications (ITDs). FLT3-ITDs confer factor-independent growth to hematopoietic cells and induce a myeloproliferative syndrome in murine bone marrow transplant models. We and others have observed that FLT3-ITD activates STAT5 and its downstream effectors, whereas ligand-stimulated wild-type FLT3 (FLT3WT) does not. In vitro mapping of tyrosine phosphorylation sites in FLT3-ITD identified 2 candidate STAT5 docking sites within the luxtamembrane domain that are disrupted by the ITD. Tyrosine to phenylalanine substitution of residues 589 and 591 in the context of the FLT3-ITD did not affect tyrosine kinase activity, but abrogated STAT5 activation. Furthermore, FLT3-ITD-Y589/591 F was incapable of inducing a myeloproliferative phenotype when transduced into primary murine bone marrow cells, whereas FLT3-ITD induced myeloproliferative disease with a median latency of 50 days. Thus, the conformational change in the FLT3 juxtamembrane domain induced by the ITD activates the kinase through dysregulation of autoinhibition and results in qualitative differences in signal transduction through STAT5 that are essential for the transforming potential of FLT3-ITD in vivo.