Chemical Genetic Identification of PKC Epsilon Substrates in Mouse Brain.

Autor:	Dugan MP; Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Ferguson LB; Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Hertz NT; Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute at the University of California San Francisco, San Francisco, California, USA; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA., Chalkley RJ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA., Burlingame AL; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA., Shokat KM; Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute at the University of California San Francisco, San Francisco, California, USA., Parker PJ; The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom., Messing RO; Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA. Electronic address: romessing@austin.utexas.edu.
Jazyk:	angličtina
Zdroj:	Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2023 Apr; Vol. 22 (4), pp. 100522. Date of Electronic Publication: 2023 Feb 28.
DOI:	10.1016/j.mcpro.2023.100522
Abstrakt:	PKC epsilon (PKCε) plays important roles in behavioral responses to alcohol and in anxiety-like behavior in rodents, making it a potential drug target for reducing alcohol consumption and anxiety. Identifying signals downstream of PKCε could reveal additional targets and strategies for interfering with PKCε signaling. We used a chemical genetic screen combined with mass spectrometry to identify direct substrates of PKCε in mouse brain and validated findings for 39 of them using peptide arrays and in vitro kinase assays. Prioritizing substrates with several public databases such as LINCS-L1000, STRING, GeneFriends, and GeneMAINA predicted interactions between these putative substrates and PKCε and identified substrates associated with alcohol-related behaviors, actions of benzodiazepines, and chronic stress. The 39 substrates could be broadly classified in three functional categories: cytoskeletal regulation, morphogenesis, and synaptic function. These results provide a list of brain PKCε substrates, many of which are novel, for future investigation to determine the role of PKCε signaling in alcohol responses, anxiety, responses to stress, and other related behaviors. Competing Interests: Conflicts of Interest The authors with the exception of K. M. S. and N. T. H declare that there are no competing interests associated with the manuscript. K. M. S. is an inventor on patents covering the analog sensitive and analog specific kinase engineering owned by Princeton University. K. M. S. has consulting agreements for the following companies, which involve monetary and/or stock compensation: Revolution Medicines, Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Mitokinin Inc, Nested, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Turning Point, Ikena, Initial Therapeutics, Vevo, and BioTheryX. N. T. H owns shares and is an employee of Mitokinin Inc. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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