Loss of PTEN binding adapter protein NHERF1 from plasma membrane in glioblastoma contributes to PTEN inactivation.
Loss of PTEN binding adapter protein NHERF1 from plasma membrane in glioblastoma contributes to PTEN inactivation.
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DOI：
10.1158/0008-5472.can-10-1271
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Georgescu MM
中科院分区：
文献类型：
--
作者：
Molina JR;Morales FC;Hayashi Y;Aldape KD;Georgescu MM
多形性胶质母细胞瘤(GBM)是一种治疗有限、预后不佳的严重脑部恶性肿瘤。抑癌基因PTEN是PI3K/Akt通路的主要抑制因子，在GBM肿瘤中经常缺失。PTEN通过使质膜上的PI3K磷脂酰肌醇底物去磷酸化而拮抗PI3K。PTEN结合接头蛋白NHERF1/EBP50在GBM中高表达，但其在肿瘤发生中的作用尚未确定。在这里，我们发现NHERF1在正常星形胶质细胞中定位于细胞膜，但在GBM肿瘤细胞中定位于细胞质。这种细胞质转移与野生型PTEN的膜分布改变平行，并伴随着Akt的连续激活。在GBM细胞中，NHERF1的膜重定位将PTEN招募到膜上，并抑制Akt的激活和细胞的增殖。相反，在膜定位NHERF1的GBM细胞中，NHERF1的耗竭增加了细胞的增殖和Akt的激活。我们的发现确定了NHERF1在质膜上的肿瘤抑制作用，并揭示了一种新的机制，即通过失去膜上定位的NHERF1而导致PTEN失活来激活PI3K/Akt。
Glioblastoma multiforme (GBM) is a severe brain malignancy with limited treatment and dismal prognosis. Tumor suppressor PTEN, the major inhibitor of the 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 but 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 they reveal a novel mechanism for PI3K/Akt activation through PTEN inactivation caused by a loss of membrane localized NHERF1.