Regulation of TORC-CREB Complex by Salt-inducible Kinases: Implications in Hypertension and Diabetes Mellitus

Cyclic AMP responsive element-binding protein (CREB) is a transcription factor coactivated in response to a simultaneous increase in intracellular CAMP and Ca2+. The target gene products of CREB involve broad physiological processes such as cell proliferation and survival, carbohydrate and lipid metabolism, steroid synthesis, and learning and memory. The newly-identified transducer of regulated CREB activity (TORC) controls transcription and expression of many CREB target genes by undergoing nucleo-cytoplasmic shuttling. Salt-inducible kinase (SIK) is a group of serine/threonine protein kinase including SIK1, SIK2 and SIK3. These kinases indirectly modulate CREB target gene transcription and expression by affecting TORC phosphorylation and their subsequent distribution between nucleus and cytoplasm. In certain organs and tissues, SIK (SIK1) is also one of the target genes for CREB. Thus, a complete negative feedback regulatory circuit may be formed between SIK and TORC-CREB complex. To date, the latter has been identified in several organs and tissues such as pancreatic beta-cell, the liver, adrenal cortex and skeletal muscle where they regulate beta-cell survival, hepatic glyconeogenesis, steroid synthesis, and mitochondrial biogenesis and fatty acid oxidation in the skeletal muscle. The feedback regulation of TORC-CREB complex by SIK and its implications in pathogenesis of hypertension and diabetes mellitus are focused on.