SIKs are serine/threonine kinasse that are part of a complex network that regulates Na,K-ATPase to maintain sodium homeostasis and blood pressure []. Vertebrates contain three forms of SIKs (SIK1-3) from three distinct genes, which display tissue-specific effects. SIK1, also called SNF1LK, controls steroidogenic enzyme production in adrenocortical cells []. In the brain, both SIK1 and SIK2 regulate energy metabolism []. SIK2, also called QIK or SNF1LK2, is involved in the regulation of gluconeogenesis in the liver and lipogenesis in adipose tissues, where it phosphorylates the insulin receptor substrate-1 []. In the liver, SIK3 (also called QSK) regulates cholesterol and bile acid metabolism []. In addition, SIK2 plays an important role in the initiation of mitosis and regulates the localization of C-Nap1, a centrosome linker protein [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the salt-inducible protein kinases, SIK1 and SIK2, which are serine/threonine-protein kinases primarily activated by the master kinase LKB1 (STK11). SIK1 is involved in a variety of processes, such as cell cycle regulation, gluconeogenesis and lipogenesis regulation and muscle growth [, , , ]. SIK2 phosphorylates insulin receptor substrate-1 (IRS1) in insulin-stimulated adipocytes, potentially modulating the efficiency of insulin signal transduction, and may have a role in the development of insulin resistance in diabetes [. SIK1/2 inhibit CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signalling [].
