[HTML][HTML] The CREB coactivator TORC2 functions as a calcium-and cAMP-sensitive coincidence detector

RA Screaton, MD Conkright, Y Katoh, JL Best… - Cell, 2004 - cell.com
RA Screaton, MD Conkright, Y Katoh, JL Best, G Canettieri, S Jeffries, E Guzman, S Niessen…
Cell, 2004cell.com
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 …
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.
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