The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.

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.
Mesh Terms:
14-3-3 Proteins, Active Transport, Cell Nucleus, Animals, Calcineurin, Calcium, Calcium Signaling, Cell Line, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Gene Expression Regulation, Glucose, Hormones, Humans, Islets of Langerhans, Macromolecular Substances, Mice, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Signal Transduction, Trans-Activators, Transcription Factors
Cell
Date: Oct. 01, 2004
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