The CREB Coactivator TORC2 Functions as a Calcium- And cAMP-sensitive Coincidence Detector

Cell. 2004 Oct 1;119(1):61-74. doi: 10.1016/j.cell.2004.09.015.

Abstract

Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB. Here, we describe a signaling module that mediates the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a CREB coactivator. This module consists of the calcium-regulated phosphatase calcineurin and the Ser/Thr kinase SIK2, both of which associate with TORC2. Under resting conditions, TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupts TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increases calcineurin activity, whereas cAMP inhibits SIK2 kinase activity. Our results illustrate how a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal cues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Calcineurin / metabolism*
  • Calcium / metabolism
  • Calcium Signaling / physiology*
  • Cell Line
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Gene Expression Regulation / genetics
  • Glucose / metabolism
  • Hormones / metabolism
  • Humans
  • Islets of Langerhans / metabolism
  • Macromolecular Substances
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering
  • Signal Transduction / physiology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • 14-3-3 Proteins
  • CRTC2 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Hormones
  • Macromolecular Substances
  • Phosphoproteins
  • RNA, Small Interfering
  • Trans-Activators
  • Transcription Factors
  • Cyclic AMP
  • salt-inducible kinase-2, mouse
  • Protein-Serine-Threonine Kinases
  • Calcineurin
  • Glucose
  • Calcium