Weng Liang-Ping, Brown Jessica L, Baker Kim M, Ostrowski Michael C, Eng Charis
Clinical Cancer Genetics Program and Human Cancer Genetics Program, Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Hum Mol Genet. 2002 Jul 15;11(15):1687-96. doi: 10.1093/hmg/11.15.1687.
The tumor suppressor PTEN possesses lipid and protein phosphatase activities. It has been well established that the lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PI3K) and Akt pathways. The precise role of the protein phosphatase activity is still unclear. In the current study, we demonstrate that overexpression of wild-type PTEN in the MCF-7 breast cancer line results in phosphatase activity-dependent decreases in the phosphorylation of ETS-2, which is a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) can lead to the phosphorylation of ETS-2, Akt and ERK1/2. The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2. In contrast, the PI3K inhibitor LY492002 has no effect on insulin-stimulated phosphorylation of ETS-2, despite the fact that it diminishes insulin-stimulated phosphorylation of Akt. Interestingly, overexpression of PTEN in MCF-7 leads to blockade of insulin-stimulated, but not EGF-stimulated, phosphorylation of ERK, accompanied by dramatic decreases in ETS-2 phosphorylation. We further show that the relationship of PTEN and ETS-2 has functional significance by demonstrating that PTEN abrogates activation of the uPA Ras-responsive enhancer, a target of ETS-2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. Our observations, therefore, suggest that PTEN blocks insulin-stimulated ETS-2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS-2 may be mediated through PTEN's protein phosphatase activity.
肿瘤抑制因子PTEN具有脂质和蛋白质磷酸酶活性。脂质磷酸酶活性通过磷酸肌醇3激酶（PI3K）和Akt信号通路对其肿瘤抑制功能至关重要，这一点已得到充分证实。蛋白质磷酸酶活性的确切作用仍不清楚。在本研究中，我们证明在MCF-7乳腺癌细胞系中过表达野生型PTEN会导致ETS-2磷酸化水平以磷酸酶活性依赖的方式降低，ETS-2是一种转录因子，其DNA结合能力受磷酸化调控。将MCF-7细胞暴露于胰岛素、胰岛素样生长因子1（IGF-1）或表皮生长因子（EGF）可导致ETS-2、Akt和ERK1/2磷酸化。MEK抑制剂PD590089可消除胰岛素刺激的ETS-2磷酸化。相反，PI3K抑制剂LY492002对胰岛素刺激的ETS-2磷酸化没有影响，尽管它能减少胰岛素刺激的Akt磷酸化。有趣的是，在MCF-7中过表达PTEN会导致胰岛素刺激的ERK磷酸化受阻，但不影响EGF刺激的ERK磷酸化，同时ETS-2磷酸化显著降低。我们进一步表明，PTEN与ETS-2的关系具有功能意义，因为我们证明PTEN以磷酸酶依赖的方式消除了uPA Ras反应增强子的激活，uPA Ras反应增强子是ETS-2作用的靶点，无论有无胰岛素。因此，我们的观察结果表明，PTEN通过独立于PI3K抑制丝裂原活化蛋白激酶（MAPK）家族的ERK成员来阻断胰岛素刺激的ETS-2磷酸化，并且PTEN对ETS-2磷酸化状态的影响可能是通过其蛋白质磷酸酶活性介导的。
