PXD015884

PXD015884 is an original dataset announced via ProteomeXchange.

Title	Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor
Description	NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.
HostingRepository	PRIDE
AnnounceDate	2020-06-24
AnnouncementXML	Submission_2020-06-23_22:34:50.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Goldfarb
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-18 01:45:44	ID requested
⏵ 1	2020-06-23 22:34:51	announced

Tamir TY, Bowman BM, Agajanian MJ, Goldfarb D, Schrank TP, Stohrer T, Hale AE, Siesser PF, Weir SJ, Murphy RM, LaPak KM, Weissman BE, Moorman NJ, Major MB, Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor. J Cell Sci, 133(14):(2020) [pubmed]

submitter keyword: BRSK2, SAD-A, BRSK1, SAD-B, NRF2, MTOR signaling, AMPK, phosphoproteomics, antioxidant response

Ben Major
contact affiliation	Washington University School of Medicine Department of Cell Biology & Physiology Washington University in St. Louis
contact email	bmajor@wustl.edu
lab head
Dennis Goldfarb
contact affiliation	Cell Biology and Physiology Institute for Informatics
contact email	d.goldfarb@wustl.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015884
     1. Label: PRIDE project
     2. Name: Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor