Department of Neuro-Oncology and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Cancer Res. 2010 Sep 1;70(17):6697-703. doi: 10.1158/0008-5472.CAN-10-1271. Epub 2010 Aug 24.
Glioblastoma multiforme (GBM) is a severe brain malignancy with limited treatment and dismal prognosis. The tumor suppressor PTEN, a major inhibitor of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, is frequently deleted in GBM tumors. PTEN antagonizes PI3K by dephosphorylating PI3K phosphoinositide substrates at the plasma membrane. The PTEN binding adapter protein NHERF1/EBP50 is overexpressed in GBM but its effects on tumorigenesis have yet to be determined. Here, we show that NHERF1 is localized to the plasma membrane in normal astrocytes and to the cytoplasm of GBM tumor cells. This cytoplasmic shift paralleled an altered membrane distribution of wild-type PTEN with consecutive Akt activation. Membrane re-targeting of NHERF1 in GBM cells recruited PTEN to the membrane and suppressed Akt activation and cell proliferation. Conversely, NHERF1 depletion in GBM cells with membrane-localized NHERF1 increased cell proliferation and Akt activation. Our findings define a tumor suppressor role for NHERF1 at the plasma membrane, and reveal a novel mechanism for PI3K/Akt activation through PTEN inactivation caused by a loss of membrane-localized NHERF1.
多形性胶质母细胞瘤（GBM）是一种严重的脑恶性肿瘤，治疗方法有限，预后不佳。肿瘤抑制因子 PTEN 是磷脂酰肌醇-3-OH 激酶（PI3K）/Akt 通路的主要抑制剂，在 GBM 肿瘤中经常缺失。PTEN 通过在质膜上磷酸化 PI3K 磷酸肌醇底物来拮抗 PI3K。PTEN 结合衔接蛋白 NHERF1/EBP50 在 GBM 中过表达，但它对肿瘤发生的影响尚未确定。在这里，我们表明 NHERF1 在正常星形胶质细胞中位于质膜上，在 GBM 肿瘤细胞的细胞质中。这种细胞质移位与野生型 PTEN 的膜分布改变平行，随后 Akt 激活。在 GBM 细胞中，NHERF1 的膜重定位将 PTEN 募集到膜上，抑制 Akt 激活和细胞增殖。相反，在膜定位的 NHERF1 的 GBM 细胞中耗尽 NHERF1 增加了细胞增殖和 Akt 激活。我们的发现定义了 NHERF1 在质膜上的肿瘤抑制作用，并揭示了一种通过膜定位的 NHERF1 缺失导致 PTEN 失活而激活 PI3K/Akt 的新机制。
