{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tamir TY"],"funding":["American Cancer Society","NIDCR NIH HHS","NIDDK NIH HHS","Howard Hughes Medical Institute","NCI NIH HHS","National Institutes of Health","NIGMS NIH HHS","Gilliam Fellowships for Advanced Study"],"pagination":["jcs241356"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7375482"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["133(14)"],"pubmed_abstract":["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."],"journal":["Journal of cell science"],"pubmed_title":["Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor."],"pmcid":["PMC7375482"],"funding_grant_id":["RO1CA216051","1F99CA245724-01","F31 DE028749","RSG-14-1657068-01-TBE","R25 GM055336","F31 CA228289","R01 CA216051","U24-DK116204-01","F32 CA225040","F31CA228289","R25-GM055336-16","F99 CA245724","T32 GM119999","T32 CA009156","5T32GM119999-03","T32 GM007040","P30 CA016086","NCI F99/K00","1F32CA225040-01","T32-GM007040-42","U24 DK116204","1F31DE028749-01","T32CA009156"],"pubmed_authors":["Stohrer T","Weissman BE","Tamir TY","Bowman BM","Murphy RM","Moorman NJ","Weir SJ","Schrank TP","Hale AE","Major MB","Goldfarb D","LaPak KM","Agajanian MJ","Siesser PF"],"additional_accession":[]},"is_claimable":false,"name":"Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor.","description":"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.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jul","modification":"2024-12-04T10:13:38.187Z","creation":"2022-02-10T20:06:58.535Z"},"accession":"S-EPMC7375482","cross_references":{"pubmed":["32546533"],"doi":["10.1242/jcs.241356"]}}