PDGFR-beta-activated ACK1-AKT signaling promotes glioma tumorigenesis.
PDGFR-beta-activated ACK1-AKT signaling promotes glioma tumorigenesis.
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PDGFR-β激活的ACK1-AKT信号传导促进胶质瘤肿瘤发生
DOI：
10.1002/ijc.29234
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发表时间：
2015
影响因子：
6.4
通讯作者：
Ge Jianwei
中科院分区：
文献类型：
--
作者：
Zhang Jiannan;Chen Tao;Mao Qin;Lin Jinbo;Jia Jun;Li Shanquan;Xiong Wenhao;Lin Yingying;Liu Zhiqiang;Liu Xiaoyu;Zhao Hailiang;Wang Guisong;Zheng Duo;Qiu Shuqi;Ge Jianwei
异常的PDGF-PDGFR信号传导及其对下游效应物的影响与胶质瘤的发展有关。一个重要的AKT调节因子，ACK 1（TNK 2）已被证明是PDGF信号传导的下游介质;然而，胶质瘤中的确切潜在机制仍然难以捉摸。在这里，我们报告说，在胶质瘤细胞中，PDGFR-β激活增强了ACK 1和AKT之间的相互作用，导致AKT激活。PDGF处理一致地促进含有PDGFR-β和ACK 1的复合物的形成。突变分析表明，ACK 1的Y 635是PDGFR-β磷酸化位点，并且ACK 1 Y 635 F突变体消除了AKT的顺序激活。此外，PDK 1在PDGF刺激期间与ACK 1相互作用，这是ACK 1与PDGFR-β结合所必需的。进一步的突变分析表明，ACK 1的T325对ACK 1和PDK 1的相互作用至关重要。ACK 1 Y 635 F或T325 A突变体消除了PDGFR-β诱导的AKT激活、随后的β-连环蛋白核转位和细胞周期蛋白D1的表达。因此，神经胶质瘤细胞周期进展、增殖和肿瘤发生被ACK 1 Y 635 F或T325 A阻断。在来自51名患者的多形性胶质母细胞瘤样本中，增加的ACK 1酪氨酸磷酸化与上调的PDGFR-β活性和AKT活化相关。总之，我们的数据表明，ACK 1在胶质瘤肿瘤发生中的PDGF-PDGFR-诱导的AKT信号传导中起着关键作用。这些知识有助于我们了解胶质瘤的进展，并可能有助于确定新的治疗靶点，为未来的胶质瘤治疗。
Aberrant PDGF‐PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR‐β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR‐β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR‐β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR‐β. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR‐β‐induced AKT activation, the subsequent nuclear translocation of β‐catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR‐β activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF‐PDGFR‐induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.