title: Akt3 is a privileged first responder in isozyme-specific electrophile response.
abstract: Isozyme-specific post-translational regulation fine tunes signaling events. However, redundancy in sequence or activity renders links between isozyme-specific modifications and downstream functions uncertain. Methods to study this phenomenon are underdeveloped. Here we use a redox-targeting screen to reveal that Akt3 is a first-responding isozyme sensing native electrophilic lipids. Electrophile modification of Akt3 modulated downstream pathway responses in cells and Danio rerio (zebrafish) and markedly differed from Akt2-specific oxidative regulation. Digest MS sequencing identified Akt3 C119 as the privileged cysteine that senses 4-hydroxynonenal. A C119S Akt3 mutant was hypomorphic for all downstream phenotypes shown by wild-type Akt3. This study documents isozyme-specific and chemical redox signal-personalized physiological responses.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Marcus J C
authors.initials: MJ
authors.lastname: Long
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Saba
authors.initials: S
authors.lastname: Parvez
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Sanjna L
authors.initials: SL
authors.lastname: Surya
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Proteomics and Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.|Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Yimon
authors.initials: Y
authors.lastname: Aye
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008055:Lipids; D010084:Oxidation-Reduction; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008055:Lipids; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt