Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2012 Mar 8;31(10):1264-74. doi: 10.1038/onc.2011.324. Epub 2011 Aug 1.
The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is activated in cancer by genetic or epigenetic events and efforts are under way to develop targeted therapies. phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is the major brake of the pathway and a common target for inactivation in glioblastoma, one of the most aggressive and therapy-resistant cancers. To achieve potent inhibition of the PI3K-Akt pathway in glioblastoma, we need to understand its mechanism of activation by investigating the interplay between its regulators. We show here that PTEN modulates the PI3K-Akt pathway in glioblastoma within a tumor suppressor network that includes Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) and pleckstrin-homology domain leucine-rich repeat protein phosphatases 1 (PHLPP1). The NHERF1 adaptor, previously characterized by our group as a PTEN ligand and regulator, shows also PTEN-independent Akt-modulating effects that led us to identify the PHLPP1/PHLPP2 Akt phosphatases as NHERF1 ligands. NHERF1 interacts via its PDZ domains with PHLPP1/PHLPP2 and scaffolds heterotrimeric complexes with PTEN. Functionally, PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects. PHLPP1 loss boosts Akt phosphorylation only in PTEN-negative cells and cooperates with PTEN loss for tumor growth. In a panel of low-grade and high-grade glioma patient samples, we show for the first time a significant disruption of all three members of the PTEN-NHERF1-PHLPP1 tumor suppressor network in high-grade tumors, correlating with Akt activation and patient's abysmal survival. We thus propose a PTEN-NHERF1-PHLPP PI3K-Akt pathway inhibitory network that relies on molecular interactions and can undergo parallel synergistic hits in glioblastoma.
磷脂酰肌醇-3-羟激酶（PI3K）-Akt 途径在癌症中通过遗传或表观遗传事件激活，目前正在努力开发靶向治疗方法。磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）肿瘤抑制因子是该途径的主要制动装置，也是胶质母细胞瘤中失活的常见靶点，胶质母细胞瘤是最具侵袭性和耐药性的癌症之一。为了在胶质母细胞瘤中实现对 PI3K-Akt 途径的有效抑制，我们需要通过研究其调节剂之间的相互作用来了解其激活机制。我们在这里表明，PTEN 在包括 Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) 和 pleckstrin-homology domain leucine-rich repeat protein phosphatases 1 (PHLPP1) 在内的肿瘤抑制网络中调节胶质母细胞瘤中的 PI3K-Akt 途径。NHERF1 接头，先前被我们小组鉴定为 PTEN 配体和调节剂，也表现出 PTEN 非依赖性 Akt 调节作用，这使我们确定 PHLPP1/PHLPP2 Akt 磷酸酶为 NHERF1 配体。NHERF1 通过其 PDZ 结构域与 PHLPP1/PHLPP2 相互作用，并与 PTEN 支架异源三聚体复合物。在功能上，PHLPP1 需要 NHERF1 进行膜定位和生长抑制作用。PHLPP1 缺失仅在 PTEN 阴性细胞中增强 Akt 磷酸化，并与 PTEN 缺失协同促进肿瘤生长。在一组低级别和高级别脑胶质瘤患者样本中，我们首次在高级别肿瘤中显示出 PTEN-NHERF1-PHLPP1 肿瘤抑制网络的所有三个成员都发生了显著破坏，与 Akt 激活和患者极差的生存相关。因此，我们提出了一个 PTEN-NHERF1-PHLPP PI3K-Akt 途径抑制网络，该网络依赖于分子相互作用，并可在胶质母细胞瘤中发生平行协同作用。
