Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor
| Autor: | Seth J. Weir, Tigist Y. Tamir, Priscila F. Siesser, Bernard E. Weissman, Trent Stohrer, M. Ben Major, Dennis Goldfarb, Brittany M. Bowman, Ryan M. Murphy, Kyle M. LaPak, Travis P. Schrank, Andrew E. Hale, Megan J. Agajanian, Nathaniel J. Moorman |
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| Rok vydání: | 2019 |
| Předmět: |
NF-E2-Related Factor 2
Biology AMP-Activated Protein Kinases Protein Serine-Threonine Kinases digestive system environment and public health 03 medical and health sciences 0302 clinical medicine Humans Kinome Protein kinase A Transcription factor PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Kinase Phosphoproteomics Receptor EphA5 Cell Biology respiratory system NFE2L2 Cell biology Oxidative Stress 030220 oncology & carcinogenesis Gain of Function Mutation Genetic screen Signal Transduction Research Article |
| Zdroj: | J Cell Sci |
| ISSN: | 1477-9137 |
| Popis: | Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied protein kinase brain-specific kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives 5′-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease. This article has an associated First Person interview with the first author of the paper. |
| Databáze: | OpenAIRE |
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