Human Mutation within Per-Arnt-Sim (PAS) Domain-containing Protein Kinase (PASK) Causes Basal Insulin Hypersecretion

Francesca Semplici, Martine Vaxillaire, Sarah Fogarty, Meriem Semache, Amelie Bonnefond, Ghislaine Fontes, Julien Philippe, Gargi Meur, Frederique Diraison, Richard B. Sessions, Jared Rutter, Vincent Poitout, Philippe Froguel, Guy A. Rutter

Research output: Contribution to journalArticle (Academic Journal)peer-review

17 Citations (Scopus)

Abstract

PAS kinase (PASK) is a glucose-regulated protein kinase involved in the control of pancreatic islet hormone release and insulin sensitivity. We aimed here to identify mutations in the PASK gene that may be associated with young-onset diabetes in humans. We screened 18 diabetic probands with unelucidated maturity-onset diabetes of the young (MODY). We identified two rare nonsynonymous mutations in the PASK gene (p.L1051V and p.G1117E), each of which was found in a single MODY family. Wild type or mutant PASKs were expressed in HEK 293 cells. Kinase activity of the affinity-purified proteins was assayed as autophosphorylation at amino acid Thr(307) or against an Ugp1p-derived peptide. Whereas the PASK p.G1117E mutant displayed a similar to 25% increase with respect to wild type PASK in the extent of autophosphorylation, and a similar to 2-fold increase in kinase activity toward exogenous substrates, the activity of the p.L1051V mutant was unchanged. Amino acid Gly(1117) is located in an alpha helical region opposing the active site of PASK and may elicit either: (a) a conformational change that increases catalytic efficiency or (b) a diminished inhibitory interaction with the PAS domain. Mouse islets were therefore infected with adenoviruses expressing wild type or mutant PASK and the regulation of insulin secretion was examined. PASK p.G1117E-infected islets displayed a 4-fold decrease in glucose-stimulated (16.7 versus 3 mM) insulin secretion, chiefly reflecting a 4.5-fold increase in insulin release at low glucose. In summary, we have characterized a rare mutation (p.G1117E) in the PASK gene from a young-onset diabetes family, which modulates glucose-stimulated insulin secretion.

Original languageEnglish
Pages (from-to)44005-44014
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number51
DOIs
Publication statusPublished - 23 Dec 2011

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