Maier D, Jones G, Li X, Schönthal A H, Gratzl O, Van Meir E G, Merlo A
Department of Research, University of CH-4031 Basel, Switzerland.
Cancer Res. 1999 Nov 1;59(21):5479-82.
The tumor suppressor PTEN negatively controls the phosphoinositide 3-kinase pathway for cell survival by dephosphorylating the phospholipid substrates phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. PTEN has been proposed to dephosphorylate focal adhesion kinase and is implicated in the regulation of cell spreading and motility. We analyzed the role of PTEN in invasion using the two highly infiltrative glioma cell lines U87MG (which lacks functional PTEN) and LN229 (wild-type PTEN). After constitutive overexpression of wild-type and phosphatase-deficient (C124S) PTEN, we found significant inhibition of invasion (50-70%) independent of the PTEN status of the cell and of the catalytic core domain of PTEN. Although wild-type but not mutant (C124S) PTEN decreased PKB/Akt phosphorylation and induced a stellate morphology in U87MG cells, an accompanying reduction of focal adhesion kinase phosphorylation was not seen. We conclude that phosphatase-independent domains of PTEN markedly reduced the invasive potential of glioma cells, defining a structural role for PTEN that regulates cell motility distinct of the PKB/Akt pathway.
肿瘤抑制因子PTEN通过使磷脂底物磷脂酰肌醇3,4 - 二磷酸和磷脂酰肌醇3,4,5 - 三磷酸去磷酸化，对细胞存活的磷酸肌醇3 - 激酶途径进行负调控。有人提出PTEN可使粘着斑激酶去磷酸化，并参与细胞铺展和运动的调节。我们使用两种高侵袭性胶质瘤细胞系U87MG（缺乏功能性PTEN）和LN229（野生型PTEN）分析了PTEN在侵袭中的作用。在组成性过表达野生型和磷酸酶缺陷型（C124S）PTEN后，我们发现侵袭受到显著抑制（50 - 70%），且与细胞的PTEN状态及PTEN的催化核心结构域无关。虽然野生型而非突变型（C124S）PTEN降低了U87MG细胞中PKB/Akt的磷酸化水平并诱导了星状形态，但并未观察到粘着斑激酶磷酸化水平随之降低。我们得出结论，PTEN的非磷酸酶结构域显著降低了胶质瘤细胞的侵袭潜能，这确定了PTEN在调节细胞运动方面的一种结构作用，该作用不同于PKB/Akt途径。
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