RGD Reference Report - Disruption of a receptor-mediated mechanism for intracellular sorting of proinsulin in familial hyperproinsulinemia. - Rat Genome Database

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Disruption of a receptor-mediated mechanism for intracellular sorting of proinsulin in familial hyperproinsulinemia.

Authors: Dhanvantari, Savita  Shen, Fu-Sheng  Adams, Tiffany  Snell, Christopher R  Zhang, ChunFa  Mackin, Robert B  Morris, Stephen J  Loh, Y Peng 
Citation: Dhanvantari S, etal., Mol Endocrinol. 2003 Sep;17(9):1856-67. doi: 10.1210/me.2002-0380. Epub 2003 Jun 26.
RGD ID: 405650689
Pubmed: PMID:12829804   (View Abstract at PubMed)
DOI: DOI:10.1210/me.2002-0380   (Journal Full-text)

In familial hyperproinsulinemia, specific mutations in the proinsulin gene are linked with a profound increase in circulating plasma proinsulin levels. However, the molecular and cellular basis for this disease remains uncharacterized. Here we investigated how these mutations may disrupt the sorting signal required to target proinsulin to the secretory granules of the regulated secretory pathway, resulting in the unregulated release of proinsulin. Using a combination of molecular modeling and site-directed mutagenesis, we have identified structural molecular motifs in proinsulin that are necessary for correct sorting into secretory granules of endocrine cells. We show that membrane carboxypeptidase E (CPE), previously identified as a prohormone-sorting receptor, is essential for proinsulin sorting. This was demonstrated through short interfering RNA-mediated depletion of CPE and transfection with a dominant negative mutant of CPE in a beta-cell line. Mutant proinsulins found in familial hyperproinsulinemia failed to bind to CPE and were not sorted efficiently. These findings provide evidence that the elevation of plasma proinsulin levels found in patients with familial hyperproinsulinemia is caused by the disruption of CPE-mediated sorting of mutant proinsulins to the regulated secretory pathway.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CpeRatinsulin processing  IMP  RGD 
CpeRatinsulin secretion involved in cellular response to glucose stimulus  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cpe  (carboxypeptidase E)


Additional Information