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RSS FeedsPeptide-based sequestration of the adaptor protein Nck1 in pancreatic {beta} cells enhances insulin biogenesis and protects against diabetogenic stresses [Signal Transduction] (Journal of Biological Chemistry)

 
 

17 august 2018 06:00:15

 
Peptide-based sequestration of the adaptor protein Nck1 in pancreatic {beta} cells enhances insulin biogenesis and protects against diabetogenic stresses [Signal Transduction] (Journal of Biological Chemistry)
 


One feature of diabetes is the failure of pancreatic ? cells to produce insulin, but the molecular mechanisms leading to this failure remain unclear. Increasing evidence supports a role for protein kinase R-like endoplasmic reticulum kinase (PERK) in the development and function of healthy pancreatic ? cells. Previously, our group identified the adaptor protein Nck1 as a negative regulator of PERK. Indeed, we demonstrated that Nck1, by directly binding PERK autophosphorylated on Tyr561, limits PERK activation and signaling. Accordingly, we found that stable depletion of Nck1 in ? cells promotes PERK activation and signaling, increases insulin biosynthesis, and improves cell viability in response to diabetes-related stresses. Herein, we explored the therapeutic potential of abrogating the interaction between Nck and PERK to improve ?-cell function and survival. To do so, we designed and used a peptide containing the minimal PERK sequence involved in binding Nck1 conjugated to the cell-permeable protein transduction domain from the HIV protein TAT. In the current study, we confirm that the synthetic TAT-Tyr(P)561 phosphopeptide specifically binds the SH2 domain of Nck and prevents Nck interaction with PERK, thereby promoting basal PERK activation. Moreover, we report that treatment of ? cells with TAT-Tyr(P)561 inhibits glucolipotoxicity-induced apoptosis, whereas it enhances insulin production and secretion. Taken together, our results support the potential of sequestering Nck using a synthetic peptide to enhance basal PERK activation and create more robust ? cells.


 
244 viewsCategory: Biochemistry
 
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