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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone β receptor
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Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone β receptor

机译：突变型甲状腺激素β受体激活磷脂酰肌醇3-激酶信号转导

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摘要

Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/ protein kinase B signaling pathway has been associated with multiple human cancers. Recently we showed that AKT is activated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma [thyroid hormone β receptor (TRβ)~(PV/PV) mice]. This TRβ~(PV/PV) mouse harbors a knock-in mutant TRβ gene (TRβPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. Here we show that in thyroid tumors, PV mutant bound significantly more to the PI3K-regulatory subunit p85α, resulting in a greater increase in the kinase activity than did TRβ1 in wild-type mice. By GST pull-down assays, the ligand-binding domain of TR was identified as the interaction site with p85α. By confocal fluorescence microscopy, p85α was shown to colocalize with TRβ1 or PV mainly in the nuclear compartment of cultured tumor cells from TRβ~pv/pv mice, but cytoplasmic p85α/PV or p85α/TRβ1 complexes were also detectable. Further biochemical analysis revealed that the activation of the PI3K-AKT-mammalian target of the rapamy-cin-p70~(S6K) pathway was observed in both the cytoplasmic and nuclear compartments, whereas the activation of the PI3K-integrin-linked kinase-matrix metalloproteinase 2 pathway was detected mainly in the extranuclear compartments. These results suggest that PV, via the activation of p85α, could act to affect PI3K downstream signaling in both the nuclear and extranuclear compartments, thereby contributing to thyroid carcinogenesis. Importantly, the present study unveils a mechanism by which a mutant TR acts to activate PI3K activity via protein-protein interactions.
机译：磷脂酰肌醇3-激酶（PI3K）-AKT /蛋白激酶B信号通路的激活与多种人类癌症有关。最近，我们发现，在滤泡性甲状腺癌小鼠模型[甲状腺激素β受体（TRβ）〜（PV / PV）小鼠]的甲状腺和转移性病变中均激活了AKT。这只TRβ〜（PV / PV）小鼠带有一个敲入突变体TRβ基因（TRβPV突变体），该基因自发地发展为甲状腺癌和与人类滤泡性甲状腺癌相似的远处转移。在这里，我们显示在甲状腺肿瘤中，PV突变体与PI3K调节亚基p85α的结合明显更多，与野生型小鼠中的TRβ1相比，激酶活性的增加更大。通过GST下拉测定法，TR的配体结合结构域被鉴定为与p85α的相互作用位点。通过共聚焦荧光显微镜观察，p85α与TRβ1或PV共定位在TRβ〜pv / pv小鼠培养的肿瘤细胞的核室中，但也可检测到细胞质p85α/ PV或p85α/TRβ1复合物。进一步的生化分析表明，在细胞质和核区室均观察到rapamy-cin-p70〜（S6K）途径的PI3K-AKT-哺乳动物靶标的激活，而PI3K-整联蛋白连接的激酶-基质的激活金属蛋白酶2途径主要在核外区室中检测到。这些结果表明，PV通过激活p85α可以影响核区和核外区室中PI3K下游信号传导，从而促进甲状腺癌变。重要的是，本研究揭示了一种机制，突变体TR可以通过该机制通过蛋白质相互作用来激活PI3K活性。

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