PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest

• Published in: Nature communications Vol. 13; no. 1; pp. 5237 - 19
• Main Authors: Yuan, Yangyang, Wang, Chenwei, Zhuang, Xuran, Lin, Shaofeng, Luo, Miaomiao, Deng, Wankun, Zhou, Jiaqi, Liu, Lihui, Mao, Lina, Peng, Wenbo, Chen, Jian, Wang, Qiangsong, Shu, Yilai, Xue, Yu, Huang, Pengyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 38/109; 38/39; 38/77; 38/88; 38/90; 38/91; 42/100; 42/109; 49/39; 631/114/2401; 631/1647/2067; 631/1647/514/1949; 631/45/475/2290; 631/80/82; 82/58; 82/80; 96/31; Algorithms; Antitumor agents; Biological activity; Cell Cycle; Cell Cycle Checkpoints - genetics; Conversion; Drug resistance; Drug Resistance, Neoplasm; Ferroptosis; Ferroptosis - genetics; Fibroblasts; Humanities and Social Sciences; Humans; Inference; Kinases; Liver; multidisciplinary; Phosphorylation; Protein Serine-Threonine Kinases; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-pim-1 - genetics; Proto-Oncogene Proteins c-pim-1 - metabolism; Science; Science (multidisciplinary); Substrates; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32976-9

Protein kinase-mediated phosphorylation plays a critical role in many biological processes. However, the identification of key regulatory kinases is still a great challenge. Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data. Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis. We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two processes. Further experiments reveal that a serine/threonine kinase, PIM1, promotes hepatic conversion and protects human dermal fibroblasts from reprogramming-induced ferroptosis and cell cycle arrest. This study not only reveals new regulatory kinases, but also provides a helpful method that might be extended to predict central kinases involved in other biological processes. Protein kinase-mediated phosphorylation plays a critical role in many biological processes. Here the authors develop a trans-omics-based algorithm called Central Kinase Inference to integrate quantitative transcriptomic and phosphoproteomic data, finding that PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest.