Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential

Salt-inducible kinases (SIKs) control the phosphorylation and subcellular localization of two key classes of transcriptional regulatory factors: class IIa histone deacetylases (HDACs) and cAMP-regulated transcriptional coactivators (CRTCs). SIK activity is inhibited by upstream signals that increase intracellular cAMP levels. cAMP-regulated SIK inhibition is a key component in the cellular effects of multiple hormones and paracrine-acting factors. Small molecule SIK inhibitors represent a novel therapeutic strategy to mimic cAMP-inducing signals in the settings of inflammatory bowel disease, osteoporosis, and skin pigmentation. Salt-inducible kinases (SIKs) represent a subfamily of AMP-activated protein kinase (AMPK) family kinases. Initially named because SIK1 (the founding member of this kinase family) expression is regulated by dietary salt intake in the adrenal gland, it is now apparent that a major biological role of these kinases is to control gene expression in response to extracellular cues that increase intracellular levels of cAMP. Here, we review four physiologically relevant examples of how cAMP signaling impinges upon SIK cellular function. By focusing on examples of cAMP-mediated SIK regulation in gut myeloid cells, bone, liver, and skin, we highlight recent advances in G protein-coupled receptor (GPCR) signal transduction. New knowledge regarding the role of SIKs in GPCR signaling has led to therapeutic applications of novel small molecule SIK inhibitors. Salt-inducible kinases (SIKs) represent a subfamily of AMP-activated protein kinase (AMPK) family kinases. Initially named because SIK1 (the founding member of this kinase family) expression is regulated by dietary salt intake in the adrenal gland, it is now apparent that a major biological role of these kinases is to control gene expression in response to extracellular cues that increase intracellular levels of cAMP. Here, we review four physiologically relevant examples of how cAMP signaling impinges upon SIK cellular function. By focusing on examples of cAMP-mediated SIK regulation in gut myeloid cells, bone, liver, and skin, we highlight recent advances in G protein-coupled receptor (GPCR) signal transduction. New knowledge regarding the role of SIKs in GPCR signaling has led to therapeutic applications of novel small molecule SIK inhibitors. Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential: (Trends Endocrinol. Metab. , 723–735, 2018)Wein et al.Trends in Endocrinology & MetabolismMarch 2, 2019In BriefThe authors of this review would like to request that a conflict of interest disclosure be added to their article. Although the article does not suggest any off label drugs, there is discussion about the potential future use of salt-inducible kinase (SIK) inhibitors for skin darkening, which is the topic of a company David E. Fisher co-founded within the past year. Full-Text PDF