The maturation and folding of secretory and transmembrane proteins begins in the endoplasmic reticulum (ER). These processes are catalyzed by an ER?resident protein?folding machinery comprising molecular chaperones, oxidoreductases, and other protein?modifying enzymes. If demand on the secretory pathway exceeds capacity, these ER?resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms. During such instances of ?ER stress,? affected cells are at increased risk for degeneration and death. Accruing evidence implicates endoplasmic reticulum (ER) stress in the etiology and pathogenesis of diabetes mellitus (both types 1 and 2) in humans. The unfolded protein response (UPR), a collection of signaling pathways that attempt to correct ER stress, has been defined and extensively studied. Under ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. However, irremediable levels of ER stress cause these adaptive measures to end, and instead usher in a terminal UPR that drives cells toward dysfunctional and diseased states, often leading to programmed cell death. We have discovered an unexpected role for the tyrosine kinase c?Abl in the UPR. The studies outlined in this proposal will explore how pharmacological modulation of this multi?domain kinase affects cellular fate under ER stress.
Stress-induced ?-cell dysfunction and death is a signature of type 2 diabetes and autoimmune-driven type 1 diabetes. Drugs that ameliorate stress-induced ?-cell dysfunction hold promise for preventing and controlling type 1 and type 2 diabetes. This project will define a new mechanism of unmitigated ?-cell stress and determine the optimal strategy for pharmacologically modulating this pathway.
| Lombard, Chloe K; Davis, Audrey L; Inukai, Takayuki et al. (2018) Allosteric Modulation of JNK Docking Site Interactions with ATP-Competitive Inhibitors. Biochemistry 57:5897-5909 |
