Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, South Korea.
School of Life Sciences, Brain Korea 21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea.
J Biol Chem. 2020 Dec 11;295(50):16906-16919. doi: 10.1074/jbc.RA120.014831. Epub 2020 Oct 15.
Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate genetic interactions. transformation of the gene into 4,653 homozygous diploid yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential interactors confirmed that , , , , , , and regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the - genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.
激酶是细胞内信号通路的关键组成部分，其在癌症中的作用已得到广泛研究。p21 激活激酶-1（PAK1）是一种丝氨酸/苏氨酸激酶，先前已涉及许多生物学过程，如细胞迁移、细胞周期进程、细胞运动、侵袭和血管生成，在神经胶质瘤和其他癌症中。然而，与 PAK1 相关的信号网络尚未完全定义。我们之前报道了一项大规模的酵母遗传相互作用筛选，以毒性作为读数来识别候选遗传相互作用。将基因转化为 4653 个纯合二倍体酵母缺失突变体，鉴定出约 400 个候选基因，这些候选基因可抑制酵母毒性。在这里，我们选择了 19 个候选遗传相互作用，这些相互作用具有人类同源物，并在神经胶质瘤中表达，以便在哺乳动物细胞、脑片培养物和原位神经胶质瘤模型中进一步研究。RNAi 和潜在相互作用物的药理学抑制证实，、、、、、、和调节 PAK1 诱导的细胞迁移，并揭示了与有丝分裂纺锤体、蛋白水解、自噬和代谢相关的基因在 PAK1 介导的神经胶质瘤细胞迁移、耐药性和增殖中的重要性。AKT1 进一步被确定为-遗传相互作用的下游介质。总之，这些数据提供了 PAK1 介导的信号转导途径的全局视图，并指出了神经胶质瘤治疗的潜在新药物靶点。
