Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation

Patrick Kelly, Candice L. Bailey, Patrick T. Fueger, Christopher B. Newgard, Patrick J. Casey, Michelle E. Kimple

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Recent studies have implicated Epac2, a guanine-nucleotide exchange factor for the Rap subfamily of monomericGproteins, as an important regulator of insulin secretion from pancreatic β-cells. Although the Epac proteins were originally identified as cAMP-responsive activators of Rap1 GTPases, the role of Rap1 in β-cell biology has not yet been defined. In this study, we examined the direct effects of Rap1 signaling on β-cell biology. Using the Ins-1 rat insulinoma line, we demonstrate that activated Rap1A, but not related monomeric G proteins, promotes ribosomal protein S6 phosphorylation. Using isolated rat islets, we show that this signaling event is rapamycin-sensitive, indicating that it is mediated by the mammalian target of rapamycin complex 1-p70 S6 kinase pathway, a known growth regulatory pathway. This newly defined β-cell signaling pathway acts downstream of cAMP, in parallel with the stimulation of cAMP-dependent protein kinase, to drive ribosomal protein S6 phosphorylation. Activated Rap1A promotes glucose-stimulated insulin secretion, islet cell hypertrophy, and islet cell proliferation, the latter exclusively through mammalian target of rapamycin complex 1, suggesting that Rap1 is an important regulator of β-cell function. This newly defined signaling pathway may yield unique targets for the treatment of β-cell dysfunction in diabetes.

Original languageEnglish (US)
Pages (from-to)15777-15785
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number21
DOIs
StatePublished - May 21 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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