Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors
Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors
复制标题
连环蛋白 delta-1 (CTNND1) 磷酸化控制星形细胞肿瘤中的间质到上皮的转变。
DOI：
10.1093/hmg/ddw253
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发表时间：
2016-10-01
影响因子：
3.5
通讯作者：
Tsang, Stephen H.
中科院分区：
文献类型：
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作者：
Yang, Jin;Bassuk, Alexander G.;Tsang, Stephen H.
TSC 1/TSC 2复合物（TSC 1/2）的失活突变会导致结节性硬化症（TSC），这是一种遗传性综合征，伴有神经系统症状和大脑中的良性错构瘤肿瘤。由于TSC效应物在人脑中很大程度上是未知的，因此使用TSC患者皮质结节来揭示TSC原代星形胶质细胞特有的过度磷酸化，所述星形胶质细胞是脑中受影响的细胞类型。我们发现了catenin delta-1 S268的异常过度磷酸化，这是可逆的mTOR特异性抑制剂。相反，在三种转移性星形细胞瘤细胞系中，S268磷酸化不足，表明S268磷酸化控制转移。TSC星形胶质细胞表现为上皮细胞（即紧密粘附、运动性较低和上皮（E）-钙粘蛋白阳性），而野生型星形胶质细胞为间充质细胞（即E-钙粘蛋白阴性和高度运动性）。尽管它们的上皮表型，TSC星形胶质细胞生长超过接触抑制，单层零星产生结节灶，一种表型阻断的mTOR抑制剂，Torin 1。此外，mTOR调节的磷酸激酶C β（PKCe）活性诱导连环蛋白δ-1 S268的磷酸化，这反过来又介导星形胶质细胞中的细胞-细胞粘附。TSC星形胶质细胞的mTOR依赖性上皮表型表明TSC 1/2和mTOR通过控制PKCe活性来调节连环蛋白δ-1的磷酸化水平，从而调节间充质-上皮转化（MET）。因此，某些形式的TSC可以用PKCe抑制剂治疗，而星形细胞瘤的转移可能被PKCe刺激剂阻断。
Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.