The roles of the PDZ-containing proteins bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass.
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.
Thomas
Melissa K
MK
Laboratory of Molecular Endocrinology and Diabetes Unit, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA. mthomas1@partners.org
Tsang
Siu Wai
SW
Yeung
Man-Lung
ML
Leung
Po Sing
PS
Yao
Kwok-Ming
KM
D048868:Adaptor Proteins, Signal Transducing / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000302:isolation & purification / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D007328:Insulin; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; C114476:PSMD9 protein, human; C402482:Psmd9 protein, rat; D015534:Trans-Activators; D046988:Proteasome Endopeptidase Complex