Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback

Lingling Duan, Melanie H. Cobb

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

In pancreatic β cells, ERK1 and ERK2 participate in nutrient sensing, and their activities rise and fall as a function of glucose concentration over the physiologic range. Glucosemetabolismtriggers calcium influx and release of calcium from intracellular stores to activate ERK1/2. Calcium influx also activates the calcium-dependent phosphatase calcineurin, which is required for maximal ERK1/2 activation by glucose. Calcineurin controls insulin gene expression by ERK1/2-dependent and -independent mechanisms. Here, we show that, in β cells, glucose activates the ERK1/2 cascade primarily through B-Raf. Glucose activation of B-Raf, like that of ERK1/2, is calcineurin-sensitive. Calcineurin binds to B-Raf in both unstimulated and stimulated cells. We show that B-Raf is a calcineurin substrate; among calcineurin target residues on B-Raf is T401, a site of negative feedback phosphorylation by ERK1/2. Blocking calcineurin activity in β cells prevents dephosphorylation of B-Raf T401 and decreases B-Raf and ERK1/2 activities. We conclude that the major calcineurin-dependent event in glucose sensing by ERK1/2 is the activation of B-Raf.

Original languageEnglish (US)
Pages (from-to)22314-22319
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number51
DOIs
StatePublished - Dec 21 2010

Keywords

  • Diabetes
  • Dimerization
  • Scaffold

ASJC Scopus subject areas

  • General

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