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TAZ negatively regulates the novel tumor suppressor ANKRD52 and promotes PAK1 dephosphorylation in lung adenocarcinomas
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2020-10-20 , DOI: 10.1016/j.bbamcr.2020.118891
Ting-Fang Lee , Ying-Pu Liu , Yen-Fan Lin , Chiung-Fang Hsu , Hsuan Lin , Wei-Chin Chang , Chih-Ming Pan , Teh-Ying Chou , Cheng-Wen Wu

Lung cancer is the leading cause of cancer death, and therefore the discovery of novel therapeutic targets is crucial. P21-activated kinase (PAK1) is an important oncogene involved in the signaling of actin cytoskeleton organization. Although PAK1 inhibition has been shown to suppress cancer progression, specific PAK1 inhibitors are not available due to the complex structure and insufficient understanding of this kinase. The Hippo signaling effector TAZ is known to be elevated in multiple human cancers and to promote cancer metastasis. This study aimed to explore the role of TAZ in regulating the tumor suppressor ankyrin repeat domain 52 (ANKRD52) and PAK1 activity. A negative correlation between TAZ and ANKRD52 was observed, with knockdown of TAZ leading to enhanced ANKRD52 promoter activity and increased mRNA levels. Moreover, reduced ANKRD52 levels were associated with late-stage lung cancer. Knockdowns of ANKRD52 resulted in elevated cell mobility, while forced ANKRD52 expression attenuated cell mobility. ANKRD52 is a subunit of the protein phosphatase 6 (PP6) holoenzyme. Mass spectrometry analysis revealed the interaction between PAK1 and the ANKRD52-PP6 complex. Knockdown of ANKRD52 or PP6c resulted in upregulated PAK1 phosphorylation. Our study demonstrates that the novel tumor suppressor protein ANKRD52 is transcriptionally inhibited by TAZ, regulating cell mobility through interactions with PP6c and dephosphorylation of PAK1.



中文翻译:

TAZ负调节新型抑癌药ANKRD52并促进肺腺癌中PAK1的去磷酸化

肺癌是癌症死亡的主要原因,因此,发现新的治疗靶标至关重要。P21激活激酶(PAK1)是重要的癌基因,参与肌动蛋白细胞骨架组织的信号传导。尽管已显示出PAK1抑制作用可抑制癌症进展,但由于其结构复杂且对该激酶的了解不足,因此无法使用特定的PAK1抑制剂。已知河马信号转导因子TAZ在多种人类癌症中升高并促进癌症转移。这项研究旨在探讨TAZ在调节抑癌锚蛋白重复域52(ANKRD52)和PAK1活性中的作用。观察到TAZ与ANKRD52之间呈负相关,敲低TAZ导致ANKRD52增强启动子活性和增加的mRNA水平。此外,降低的ANKRD52水平与晚期肺癌有关。敲低ANKRD52导致细胞迁移率升高,而强迫的ANKRD52表达减弱细胞迁移率。ANKRD52是蛋白磷酸酶6(PP6)全酶的一个亚基。质谱分析揭示了PAK1和ANKRD52-PP6复合物之间的相互作用。敲低ANKRD52或PP6c导致PAK1磷酸化上调。我们的研究表明,新型肿瘤抑制蛋白ANKRD52被TAZ转录抑制,通过与PP6c的相互作用和PAK1的去磷酸化来调节细胞的活动性。

更新日期:2020-11-15
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