A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity.
A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity.
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DOI：
10.1038/ncomms9093
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发表时间：
2015-08-26
影响因子：
16.6
通讯作者：
Larue L
中科院分区：
文献类型：
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作者：
Conde-Perez A;Gros G;Longvert C;Pedersen M;Petit V;Aktary Z;Viros A;Gesbert F;Delmas V;Rambow F;Bastian BC;Campbell AD;Colombo S;Puig I;Bellacosa A;Sansom O;Marais R;Van Kempen LC;Larue L
肿瘤抑制因子PTEN的缺失在人黑色素瘤中是常见的，导致MAPK活化，抑制衰老并介导转移行为。PTEN缺失如何介导这些效应尚不清楚。在此，我们发现，上皮细胞和黑素细胞系中PTEN的缺失诱导了β-连环蛋白的核定位和转录激活，而不依赖于PI 3 K-AKT-GSK 3 β轴。PTEN的缺失导致小窝蛋白-1（caveolin-1，CAV 1）依赖的β-catenin在体外的转录调节，与NRASQ 61 K协同启动体内黑色素瘤的发生，并诱导与E-cadherin内化相关的有效转移形成。CAV 1-β-catenin轴由反馈环介导，其中β-catenin抑制miR-199 a-5 p和miR-203的转录，其抑制黑素瘤细胞中的CAV 1 mRNA水平。这些数据揭示了一种机制，通过这种机制，PTEN的缺失增加了CAV 1介导的β-连环蛋白与膜E-钙粘蛋白的解离，这可能促进衰老旁路和转移。 PTEN突变是黑色素原性的机制由于不同细胞位置中的不同PTEN功能而复杂化。在这里，作者确定了膜PI 3 K-AKT信号传导的替代方案，这是一种小窝蛋白-1依赖性PTEN通路，可诱导β-连环蛋白的核定位和激活。
Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K–AKT–GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRASQ61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β–catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis. The mechanism by which PTEN mutation is melanomagenic is complicated by different PTEN functions in different cellular locations. Here, the authors identify an alternative to membrane PI3K–AKT signalling, a caveolin-1-dependent PTEN pathway that induces nuclear localization and activation of β-catenin.