DYRK1A aggravates β cell dysfunction and apoptosis by promoting the phosphorylation and degradation of IRS2

Exp Gerontol. 2019 Oct 1:125:110659. doi: 10.1016/j.exger.2019.110659. Epub 2019 Jul 13.

Abstract

In this study, we aimed to investigate the role of dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), which is one of the most important regulators of Alzheimer's disease development, in islet β cell dysfunction and apoptosis. We found significantly increased expression of DYRK1A in both the hippocampus and pancreatic islets of APPswe/PS1ΔE9 transgenic mice than in wild-type littermates. Furthermore, we observed that the overexpression of DYRK1A greatly aggravated β cell apoptosis. Most importantly, we found that DYRK1A directly interacted with insulin receptor substrate-2 (IRS2) and promoted IRS2 phosphorylation, leading to the proteasomal degradation of IRS2 and promotion of β cell dysfunction and apoptosis. These findings suggested that DYRK1A is a potential drug target in diabetes mellitus.

Keywords: Alzheimer's disease; Apoptosis; DYRK1A; Diabetes mellitus; IRS2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology*
  • Animals
  • Apoptosis
  • Diabetes Complications / etiology
  • Diabetes Complications / therapy*
  • Dyrk Kinases
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*

Substances

  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases