| First Author | Kefalas G | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 32 | Pages | 12516-12524 |
| PubMed ID | 29941454 | Mgi Jnum | J:269664 |
| Mgi Id | MGI:6220502 | Doi | 10.1074/jbc.RA118.002728 |
| Citation | Kefalas G, et al. (2018) Peptide-based sequestration of the adaptor protein Nck1 in pancreatic beta cells enhances insulin biogenesis and protects against diabetogenic stresses. J Biol Chem 293(32):12516-12524 |
| abstractText | One feature of diabetes is the failure of pancreatic beta 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 beta 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 Tyr(561), limits PERK activation and signaling. Accordingly, we found that stable depletion of Nck1 in beta 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 beta-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 beta 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 beta cells. |
