Salk Institute for Biological Studies has been awarded US Patent 7,485,434, “Method for screening compounds for those that modulate transducers of regulated CREB activity.”
The inventor listed on the patent is Marc Montminy.
Glucose and incretin hormones promote pancreatic islet cell survival via the calcium- and cAMP-dependent induction, respectively, of the transcription factor CREB. Specifically, a signaling module has been identified which mediates cooperative effects of calcium and cAMP on islet cell gene expression by stimulating the dephosphorylation and nuclear entry of transducer of regulated CREB activity 2, or TORC2, a cytoplasmic CREB coactivator. The patent claims a module comprising a cAMP-regulated snf1-like kinase called SIK2 and the calcium-regulated phosphatase calcineurin, both of which associate with TORC2 in the cytoplasm.
TORC2 is repressed under basal conditions through a phosphorylation-dependent interaction with 14-3-3 proteins. cAMP and calcium signals stimulate CREB target gene expression via complementary effects on TORC2 dephosphorylation; cAMP disrupts TORC2-associated activity of SIK2 or related kinases, whereas calcium induces TORC2 dephosphorylation via calcineurin. As stated in the abstract, these findings provide a novel mechanism by which CREB activates cellular gene expression, depending on nutrient and energy status, and facilitate development of assays to identify compounds which modulate the role of TORCs.
Fasting and energy-sensing pathways regulate the gluconeogenic program in the liver by modulating the nuclear entry of TORC2. Hepatic TORC2 over-expression induces fasting hyperglycemia, whereas knockdown of TORC2 leads to fasting hypoglycemia and silencing of the gluconeogenic program. Since many patients with type 2 diabetes exhibit fasting hyperglycemia due to elevated hepatic gluconeogenesis, compounds that enhance TORC2 phosphorylation may be appropriate therapeutic agents in this setting.