Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591
Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591
复制标题
致癌突变体的转化和 FLT3 野生型的配体依赖性激活需要酪氨酸残基 589 和 591
DOI：
--
复制
发表时间：
2008
影响因子：
11.5
通讯作者：
K. Spiekermann
中科院分区：
文献类型：
--
作者：
S. Vempati;C. Reindl;U. Wolf;Ruth Kern;Konstantin Petropoulos;V. Naidu;C. Buske;W. Hiddemann;Tobias M. Kohl;K. Spiekermann
目的：在高达30%的急性髓性白血病患者中发现受体酪氨酸激酶FLT 3的突变，并且与较差的预后相关。在这项研究中，我们的特点是关键的酪氨酸残基负责转化潜力的活性FLT 3受体突变体和配体依赖性激活FLT 3-WT。试验设计：我们对FLT 3-D835 Y酪氨酸激酶结构域（TKD）突变体中假定的自磷酸化酪氨酸残基进行了详细的结构-功能分析。将FLT 3-D835 Y构建体的跨膜结构域（Y 566、Y 572、Y 589、Y 591、Y 597和Y 599）、激酶间结构域（Y 726和Y 768）和COOH末端结构域（Y 955和Y 969）中的所有酪氨酸残基连续突变为苯丙氨酸，并在白细胞介素-3依赖性Ba/F3细胞中分析这些突变体的转化活性。还在FLT 3内部串联重复突变体（FLT 3-ITD）和FLT 3野生型（FLT 3-WT）受体中分析了对FLT 3-D835 Y转化潜力至关重要的酪氨酸残基。测试结果：酪氨酸残基被苯丙氨酸在质膜，激酶间，和COOH-末端结构域的取代导致FLT 3-D835 Y表达细胞的转化潜力的完全丧失，这可以归因于信号转导和转录激活因子5（STAT 5）磷酸化在分子水平上的显着减少。重新引入单个酪氨酸残基揭示了Y 589和Y 591在重建FLT 3-TKD表达细胞的白细胞介素-3非依赖性生长中的关键作用。Y 589和Y 591突变为苯丙氨酸的组合突变也消除了FLT 3-WT的配体依赖性增殖和FLT 3-ITD的转化潜力，随后消除了STAT 5磷酸化。结论：我们确定了两个酪氨酸残基，Y 589和Y 591，在质膜结构域，这是关键的配体依赖性激活的FLT 3-WT和致癌FLT 3突变体的转化潜力。
Purpose: Mutations in the receptor tyrosine kinase FLT3 are found in up to 30% of acute myelogenous leukemia patients and are associated with an inferior prognosis. In this study, we characterized critical tyrosine residues responsible for the transforming potential of active FLT3-receptor mutants and ligand-dependent activation of FLT3-WT. Experimental Design: We performed a detailed structure-function analysis of putative autophosphorylation tyrosine residues in the FLT3-D835Y tyrosine kinase domain (TKD) mutant. All tyrosine residues in the juxtamembrane domain (Y566, Y572, Y589, Y591, Y597, and Y599), interkinase domain (Y726 and Y768), and COOH-terminal domain (Y955 and Y969) of the FLT3-D835Y construct were successively mutated to phenylalanine and the transforming activity of these mutants was analyzed in interleukin-3-dependent Ba/F3 cells. Tyrosine residues critical for the transforming potential of FLT3-D835Y were also analyzed in FLT3 internal tandem duplication mutants (FLT3-ITD)and the FLT3 wild-type (FLT3-WT) receptor. Result: The substitution of the tyrosine residues by phenylalanine in the juxtamembrane, interkinase, and COOH-terminal domains resulted in a complete loss of the transforming potential of FLT3-D835Y-expressing cells which can be attributed to a significant reduction of signal tranducer and activator of transcription 5 (STAT5) phosphorylation at the molecular level. Reintroduction of single tyrosine residues revealed the critical role of Y589 and Y591 in reconstituting interleukin-3-independent growth of FLT3-TKD-expressing cells. Combined mutation of Y589 and Y591 to phenylalanine also abrogated ligand-dependent proliferation of FLT3-WT and the transforming potential of FLT3-ITD-with a subsequent abrogation of STAT5 phosphorylation. Conclusion: We identified two tyrosine residues, Y589 and Y591, in the juxtamembrane domain that are critical for the ligand-dependent activation of FLT3-WT and the transforming potential of oncogenic FLT3 mutants.
登录
查看更多内容
影响因子：
11.2
作者：
Z. Xia;M. Baer;A. Block;H. Baumann;M. Wetzler
通讯作者：
Z. Xia;M. Baer;A. Block;H. Baumann;M. Wetzler
DOI：
10.1006/bbrc.2000.3662
发表时间：
2000-10-14
影响因子：
3.1
作者：
Zhang, SL;Broxmeyer, HE
通讯作者：
Broxmeyer, HE
影响因子：
20.3
作者：
Rocnik, Jennifer L.;Okabe, Rachel;Gilliland, D. Gary
通讯作者：
Gilliland, D. Gary
肝细胞生长因子可降低 EGFR-T790M 突变型肺癌对不可逆表皮生长因子受体抑制剂的敏感性。
影响因子：
11.5
作者：
Yamada T;Yano S;et al.
通讯作者：
et al.