Peptide-based sequestration of the adaptor protein Nck1 in pancreatic β cells enhances insulin biogenesis and protects against diabetogenic stresses

J Biol Chem. 2018 Aug 10;293(32):12516-12524. doi: 10.1074/jbc.RA118.002728. Epub 2018 Jun 25.


One feature of diabetes is the failure of pancreatic β 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 β 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 β 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 β-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 β 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 β cells.

Keywords: PERK; adaptor protein; adaptor protein Nck; beta cell (B-cell); cell therapy; cell-penetrating peptide; diabetes; insulin secretion; insulin synthesis; lipotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Cells, Cultured
  • Diabetes Mellitus / physiopathology*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / prevention & control
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / pathology
  • Insulinoma / genetics
  • Insulinoma / metabolism
  • Insulinoma / prevention & control*
  • Mice
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peptide Fragments / pharmacology*
  • Phosphorylation
  • Protective Agents / pharmacology*
  • Signal Transduction
  • Stress, Physiological
  • eIF-2 Kinase / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Insulin
  • Nck protein
  • Oncogene Proteins
  • Peptide Fragments
  • Protective Agents
  • PERK kinase
  • eIF-2 Kinase