Secreted PDZD2 exerts an insulinotropic effect on INS-1E cells by a PKA-dependent mechanism

Mol Cell Endocrinol. 2020 Dec 1;518:111026. doi: 10.1016/j.mce.2020.111026. Epub 2020 Sep 9.


Secreted PDZD2 (sPDZD2) is a signaling molecule generated upon proteolytic processing of the multi-PDZ-containing protein PDZD2. Previous analysis of gene-trap mice deficient in the synthesis of full-length PDZD2, but not the secreted form, revealed a role of PDZD2 in the regulation of glucose-stimulated insulin secretion. Here, using the pancreatic INS-1E β cells as in vitro model, we showed that depletion of PDZD2/sPDZD2 by RNA interference suppressed the expression of β-cell genes Ins1, Glut2 and MafA whereas treatment with recombinant sPDZD2 rescued the suppressive effect. Similar to GLP-1, sPDZD2 stimulated intracellular cAMP levels, activated β-cell gene expression in a PKA-dependent manner and induced the phosphorylation and nuclear localization of PDX1. Depletion of PDX1 inhibited the sPDZD2 insulinotropic effect, which could also be demonstrated in mouse islets. In summary, our findings are consistent with sPDZD2 serving a signaling function in regulating β-cell gene expression.

Keywords: INS-1E; Insulin; PDX1; PDZD2; PKA; Secreted PDZD2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / pharmacology*
  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Adhesion Molecules / pharmacology*
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Glucose Transporter Type 2 / genetics
  • Glucose Transporter Type 2 / metabolism
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Secretion / drug effects*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Mice
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Rats
  • Secretory Pathway / drug effects
  • Secretory Pathway / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Adaptor Proteins, Signal Transducing
  • Cell Adhesion Molecules
  • Glucose Transporter Type 2
  • Ins1 protein, mouse
  • Insulin
  • PDZD2 protein, rat
  • Pdzd2 protein, mouse
  • RNA, Small Interfering
  • Cyclic AMP-Dependent Protein Kinases