Jun Hyun Jung, Paulo Joao A, Appleman Victoria A, Yaron-Barir Tomer M, Johnson Jared L, Yeo Alan T, Rogers Vaughn A, Kuang Shan, Varma Hemant, Gygi Steven P, Trotman Lloyd C, Charest Al
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
iScience. 2024 Oct 28;27(12):111278. doi: 10.1016/j.isci.2024.111278. eCollection 2024 Dec 20.
PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies are missense mutations that have not been thoroughly examined. Here, we leveraged genetically modified mice and isogenic astrocyte cell cultures to investigate the role of clinically relevant mutations (G36E, L42R, C105F, and R173H) in the development of EGFR-driven GBM. We report that the loss of tumor suppression from these mutants is unrelated to their lipid phosphatase activity and rather relate to elevated localization at the cell membrane. Moreover, expression of these PTEN mutations heightened EGFR activity by sequestering EGFR within endomembranes longer and affected its signaling behavior. Through comprehensive studies on global protein phosphorylation and kinase library analyses in cells with the G36E and L42R PTEN mutations, we identified distinct cancer-promoting pathways activated by EGFR, offering targets for treating GBM with these PTEN alterations.
PTEN在预防胶质母细胞瘤（GBM，一种严重且无法治愈的脑癌）的发展中起着关键作用。在GBM中，大多数PTEN缺陷是错义突变，尚未得到充分研究。在此，我们利用基因改造小鼠和同基因星形胶质细胞培养物，研究临床相关突变（G36E、L42R、C105F和R173H）在表皮生长因子受体（EGFR）驱动的GBM发展中的作用。我们报告称，这些突变体肿瘤抑制功能的丧失与其脂质磷酸酶活性无关，而是与细胞膜上定位增加有关。此外，这些PTEN突变的表达通过将EGFR更长时间地隔离在内膜中增强了EGFR活性，并影响其信号传导行为。通过对具有G36E和L42R PTEN突变的细胞进行全球蛋白质磷酸化的全面研究和激酶文库分析，我们确定了由EGFR激活的不同促癌途径，为治疗具有这些PTEN改变的GBM提供了靶点。
