Regulation of CREB-mediated gene expression by salt inducible kinase.

Salt inducible kinase (SIK) was identified as a molecule induced in the adrenal glands of rats fed with a high-salt diet. A major downstream of SIK is regulation of camp-responsive element (CRE)-dependent gene expression. SIK represses the activity of CRE-binding protein (CREB) by phosphorylating a CREB-specific co-activator transducer of regulated CREB activity (TORC). When TORC is dephosphorylated it activates CREB in a CREB-phosphorylation independent manner. The importance of the dephosphorylation of TORC has been suggested by the fact that a kinase inhibitor staurosporine induces dephosphorylation of TORC and upregulates the gene expression of CYP11A, CYP11B1, CYP11B2 and StAR in adrenocortical cells. The identification of SIK caused a stir in the field of CREB studies and led to disclosure of cascades hidden behind the classical mechanism for CREB activity.