The roles of the PDZ-containing proteins bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass

Curr Protein Pept Sci. 2009 Feb;10(1):30-6. doi: 10.2174/138920309787315248.

Abstract

PDZ domains are versatile protein interaction modules with the ability to dimerize and to recognize internal and carboxy-terminal peptide motifs. Their function in mediating the formation of multi-molecular signaling complexes is best understood at neuronal and epithelial membranes. In a screen for interactors that regulate transcription factor function in pancreatic beta cells, we isolated two PDZ-containing proteins Bridge-1 (PSMD9) and PDZD2, which contain one and six PDZ domains, respectively. Here, we review their functions in the regulation of pancreatic beta cells as a nuclear coactivator or extracellular signaling molecule. Bridge-1 interacts with both E12 and PDX-1 to stimulate insulin promoter activity. Recent gain-of-function analysis in both cell and transgenic models has revealed its functions to regulate both insulin gene expression and pancreatic beta-cell survival. Little is known about the intracellular function of PDZD2 that is predominantly localized to the endoplasmic reticulum of INS-1E cells. Interestingly, PDZD2 is proteolytically processed by caspase-3 to generate a carboxy-terminal secreted protein (sPDZD2) containing two PDZ domains. Expressed in fetal pancreatic progenitor and INS-1E cells, sPDZD2 when added as recombinant protein exerts concentration-dependent mitogenic effects on beta-like cells. We propose that the PDZ domain proteins Bridge-1 and PDZD2 likely transduce signals that regulate insulin production, proliferation, and survival of pancreatic beta cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / isolation & purification
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Adhesion Molecules
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / chemistry
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism
  • Neoplasm Proteins / isolation & purification
  • Neoplasm Proteins / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / isolation & purification
  • Proteasome Endopeptidase Complex / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / isolation & purification
  • Trans-Activators / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Adhesion Molecules
  • Insulin
  • Neoplasm Proteins
  • PDZD2 protein, human
  • PSMD9 protein, human
  • Psmd9 protein, rat
  • Trans-Activators
  • Proteasome Endopeptidase Complex