Nguyen H-N, Yang J-M, Rahdar M, Keniry M, Swaney K F, Parsons R, Park B H, Sesaki H, Devreotes P N, Iijima M
Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Oncogene. 2015 Jul;34(28):3737-43. doi: 10.1038/onc.2014.293. Epub 2014 Sep 29.
Phosphatase and tensin homolog (PTEN), which negatively regulates tumorigenic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, is a commonly mutated tumor suppressor. The majority of cancer-associated PTEN mutations block its essential PIP3 phosphatase activity. However, there is a group of clinically identified PTEN mutations that maintain enzymatic activity, and it is unknown how these mutations contribute to tumor pathogenesis. Here, we show that these enzymatically competent PTEN mutants fail to translocate to the plasma membrane where PTEN converts PIP3 to PI(4,5)P2. Artificial membrane tethering of the PTEN mutants effectively restores tumor suppressor activity and represses excess PIP3 signaling in cells. Thus, our findings reveal a novel mechanism of tumorigenic PTEN deficiency.
磷酸酶和张力蛋白同源物（PTEN）是一种常见的突变型肿瘤抑制因子，它对致癌性磷脂酰肌醇（3,4,5）-三磷酸（PIP3）信号通路起负调控作用。大多数与癌症相关的PTEN突变会阻断其关键的PIP3磷酸酶活性。然而，有一组临床鉴定出的PTEN突变仍保留酶活性，而这些突变如何导致肿瘤发病机制尚不清楚。在此，我们表明这些具有酶活性的PTEN突变体无法转运至质膜，而PTEN在质膜处将PIP3转化为PI(4,5)P2。PTEN突变体的人工膜拴系可有效恢复肿瘤抑制活性，并抑制细胞中过量的PIP3信号传导。因此，我们的研究结果揭示了致癌性PTEN缺陷的一种新机制。
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