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 41944, Korea.
School of Life Sciences, Brain Korea 21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea.
Cells. 2020 May 7;9(5):1156. doi: 10.3390/cells9051156.
Kinases are critical intracellular signaling proteins. To better understand kinase-mediated signal transduction, a large-scale human-yeast genetic interaction screen was performed. Among 597 human kinase genes tested, 28 displayed strong toxicity in yeast when overexpressed. transformation of these toxic kinase genes into 4653 homozygous diploid yeast deletion mutants followed by barcode sequencing identified yeast toxicity modifiers and thus their human orthologs. Subsequent network analyses and functional grouping revealed that the 28 kinases and their 676 interaction partners (corresponding to a total of 969 genetic interactions) are enriched in cell death and survival (34%), small-molecule biochemistry (18%) and molecular transport (11%), among others. In the subnetwork analyses, a few kinases were commonly associated with glioma, cell migration and cell death/survival. Our analysis enabled the creation of a first draft of the kinase genetic interactome network and identified multiple drug targets for inflammatory diseases and cancer, in which deregulated kinase signaling plays a pathogenic role.
激酶是细胞内信号转导的关键蛋白。为了更好地理解激酶介导的信号转导，进行了大规模的人类-酵母遗传相互作用筛选。在测试的 597 个人类激酶基因中，有 28 个在过表达时在酵母中表现出强烈的毒性。将这些毒性激酶基因转化为 4653 个纯合二倍体酵母缺失突变体，然后进行条形码测序，鉴定出酵母毒性调节剂及其人类同源物。随后的网络分析和功能分组表明，这 28 个激酶及其 676 个相互作用伙伴（对应于总共 969 个遗传相互作用）在细胞死亡和存活（34%）、小分子生物化学（18%）和分子运输（11%）等方面富集。在子网络分析中，有几个激酶与神经胶质瘤、细胞迁移和细胞死亡/存活有关。我们的分析创建了激酶遗传相互作用网络的初稿，并确定了多个炎症性疾病和癌症的药物靶点，其中失调的激酶信号转导起着致病作用。
