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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 333-338 |
| Number of pages | 6 |
| Journal | Nature Chemical Biology |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2017 |
Funding
We thank J. Fetcho and B. Miller (Cornell University) for scientific and technical guidance on zebrafish studies; J. Zhang (University of California, San Diego) and Johns Hopkins University for providing AktAR reporter plasmid; J. Poganik for his initial contributions to zebrafish studies; the zebrafish husbandry and microinjection/imaging facility (NIH R01 NS026593, J. Fetcho (Cornell University)), the Cornell NMR facility (NSF MRI: CHE-1531632, Y.A.), the Cornell Imaging Center (NIH 1S10RR025502, R.M. Williams (Cornell University)) and the Cornell proteomics and MS facility (NIH 1S10RR025449-01, S.Z.) for instrumentation. Supported by NIH New Innovator (1DP2GM114850), Beckman Young Investigator, NSF CAREER (CHE-1351400), Burroughs Wellcome CRTG and Sloan Fellowship programs (to Y.A.); HHMI predoctoral fellowship (59108350 to S.P.) and a Hill undergraduate fellowship (to S.L.S.) for student support.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology