Lipid‐derived electrophiles regulate isoform‐specific redox‐dependent kinase signaling

Abstract

Akt is a serine/threonine‐specific kinase and a master regulator of metabolism, proliferation and apoptosis. Isoform‐specific deregulation of Akt plays a key role in distinct tumor phenotypes. Pan‐Akt inhibitors such as MK‐2206 are currently in clinical trials for cancer therapy, further highlighting the clinical significance of understanding Akt regulation and innovating novel tools to inhibit its activity. However, methods to develop isozyme‐specific therapeutics have remained elusive, due to large sequence homology and functional similarity among the three Akt isozymes, Akt1, 2 and 3. Recently, in a collaborative study with my graduate student and postdoc mentors (Long et al. Nature Chemical Biology 2016 accepted), we discovered that Akt3 is a privileged responder to 4‐hydroxynonenal (HNE), a bioactive lipid‐derived electrophilic signal. Target‐specific electrophilic modification of a cysteine residue (C119) unique to Akt3 resulted in downregulation of Akt3 activity in mammalian cells as well as in zebrafish. This modification alone was sufficient to upregulate endogenous downstream pro‐apoptotic genes. Akt1 and Akt2 were both unresponsive under otherwise identical conditions. My independent research will build on this discovery to investigate the functional impacts of HNE modification of a non‐cysteine residue, which we had recently discovered is also modified by HNE. This residue is also unique to Akt3. My preliminary data suggests that a functional mutation of this residue results in upregulation of Akt3 kinase activity. We are now making headway towards examining the effects of this non‐cysteine site‐specific electrophilic modification on downstream targets of Akt3 using chemical biology and genetic approaches in cultured cells and zebrafish that are well established in our laboratory. Further investigations in this area promises to reveal intricate regulatory mechanisms of kinase isozymes by endogenous lipid‐derived electrophiles, ultimately aiding in the development of isozyme‐specific drugs.Support or Funding InformationWe acknowledge the Hill Fellowship for Undergraduate Summer Research to Sanjna Surya, HHMI pre‐doctoral fellowship to Saba Parvez, and NIH New Innovator Award (1DP2GM114850), Beckman Young Investigator, NSF CAREER (CHE‐1351400), Burroughs Wellcome CRTG, and Sloan Fellowship programs to Yimon Aye for research support.