FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells
FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells
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DOI：
10.1038/sj.leu.2404923
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发表时间：
2007-12-01
期刊：
影响因子：
11.4
通讯作者：
Trepel, J. B.
中科院分区：
文献类型：
--
作者：
Kajiguchi, T.;Chung, E. J.;Trepel, J. B.
细胞核β-连环蛋白的失调积累增强β-连环蛋白靶基因的转录并促进恶性转化。最近，急性髓性白血病（AML）细胞与激活突变的FMS样酪氨酸激酶-3（FLT 3）被报道显示升高的β-连环蛋白依赖的核信号。已显示β-连环蛋白的酪氨酸磷酸化促进其核定位。在这里，我们研究了FLT 3活性和β-连环蛋白核定位之间的因果关系。与具有野生型FLT 3（FLT 3-WT）的细胞相比，具有FLT 3内部串联重复（FLT 3-ITD）和酪氨酸激酶结构域突变（FLT 3-TKD）的细胞具有升高的酪氨酸磷酸化β-连环蛋白水平。虽然β-连环蛋白在FLT 3-WT细胞中主要定位于细胞质中，但在FLT 3-ITD细胞中主要定位于细胞核中。用FLT 3激酶抑制剂处理或用RNAi沉默FLT 3降低了β-连环蛋白酪氨酸磷酸化和核定位。相反，用FLT 3配体处理FLT 3-WT细胞增加了β-连环蛋白的酪氨酸磷酸化和核积累。内源性β-连环蛋白与内源性活化的FLT 3共免疫沉淀，重组活化的FLT 3直接磷酸化重组β-连环蛋白。最后，FLT 3抑制剂降低了从FLT 3-ITD阳性AML患者获得的白血病细胞中β-连环蛋白的酪氨酸磷酸化。这些数据表明，FLT 3激活诱导β-连环蛋白酪氨酸磷酸化和核定位，因此表明AML中FLT 3激活和β-连环蛋白致癌信号传导相关的机制。
Deregulated accumulation of nuclear beta-catenin enhances transcription of beta-catenin target genes and promotes malignant transformation. Recently, acute myeloid leukemia (AML) cells with activating mutations of FMS-like tyrosine kinase-3 (FLT3) were reported to display elevated beta-catenin-dependent nuclear signaling. Tyrosine phosphorylation of beta-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and beta-catenin nuclear localization. Compared to cells with wild-type FLT3 (FLT3-WT), cells with the FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) had elevated levels of tyrosine-phosphorylated beta-catenin. Although beta-catenin was localized mainly in the cytoplasm in FLT3-WT cells, it was primarily nuclear in FLT3-ITD cells. Treatment with FLT3 kinase inhibitors or FLT3 silencing with RNAi decreased beta-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of beta-catenin. Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.