C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration
C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration
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DOI：
10.1096/fj.04-2532fje
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Dahlbäck, B
中科院分区：
文献类型：
--
作者：
Hafizi, S;Ibraimi, F;Dahlbäck, B
我们以前已经确定了C1结构域的磷酸酶和TENSin同源物（C1-TEN）作为细胞内结合伙伴的Axl受体酪氨酸激酶（RTK）。C1-TEN是一种张力蛋白相关蛋白，其N-末端区域与PTEN具有预测的结构相似性。在这里，我们报告了我们的观察C1-TEN在HEK 293细胞中异位表达的影响，这导致了深刻的分子和表型变化。C1-TEN的稳定表达改变了细胞形态，细胞伸展减少，丝状肌动蛋白染色减弱。过表达C1-TEN的细胞增殖和迁移速率与模拟转染细胞相比受到极大抑制。此外，血清饥饿诱导的细胞凋亡引起的caspase 3的活性增加了两倍，在C1-TEN过表达细胞与模拟细胞。此外，C1-TEN过表达细胞显示Akt/PKB激酶及其底物GSK 3的磷酸化显著降低，Akt酶活性也降低。未观察到对JNK的此类影响。此外，血清刺激的Akt激活延迟C1-TEN过表达细胞，而ERK激活的配置文件没有观察到差异。此外，表达C1-TEN突变体的细胞显示细胞增殖和Akt活化的完全恢复，其中在位置231处的推定的磷酸酶活性位点半胱氨酸被丝氨酸取代。总之，C1-TEN似乎是一种新的细胞内磷酸酶，负调节Akt/PKB信号级联反应，在这方面与其相关的PTEN相似。然而，C1-TEN的特定结构域组织可能使其能够以独特的方式调节RTK和与Akt/PKB信号传导相关的其他信号传导复合物。
We have previously identified C1 domain-containing phosphatase and TENsin homologue (C1-TEN) as being an intracellular binding partner for Axl receptor tyrosine kinase (RTK). C1-TEN is a tensin-related protein that houses an N-terminal region with predicted structural similarity to PTEN. Here, we report our observations on the effects of ectopic expression of C1-TEN in HEK293 cells, which resulted in profound molecular and phenotypic changes. Stable expression of C1-TEN altered cellular morphology, with less cell spreading and weaker filamentous actin staining. Cells overexpressing C1-TEN were inhibited greatly in their proliferation and migration rates as compared with mock-transfected cells. Furthermore, serum starvation-induced apoptosis caused a twofold increase in caspase 3 activity in C1-TEN-overexpressing cells vs. mock cells. In addition, C1-TEN-overexpressing cells showed a markedly reduced phosphorylation of Akt/PKB kinase and its substrate GSK3, as well as reduced Akt enzymatic activity. No such effects on JNK were observed. Also, serum-stimulated activation of Akt was delayed in C1-TEN-overexpressing cells, while no difference in profile of ERK activation was observed. Furthermore, cells expressing a C1-TEN mutant where the putative phosphatase active site cysteine at position 231 was substituted for a serine displayed full restoration of both cell proliferation and Akt activation. In conclusion, C1-TEN appears to be a novel intracellular phosphatase that negatively regulates the Akt/PKB signaling cascade, and is similar to its relative PTEN in this respect. However, the particular domain organization of C1-TEN may enable it to regulate RTK and other signaling complexes that are linked to Akt/PKB signaling in a unique manner.