Within the AMPK family, the subfamily of salt inducible kinases (SIKs) contains three kinases (SIK1–3). SIK1, the founding member of this subfamily, was identified and named as a kinase whose expression is induced in the adrenal gland of rats fed a high salt diet. Subsequent homology searches led to the identification of SIK2 and SIK3. All three SIK family members share a characteristic structure, including an N-terminal kinase domain bearing a LKB1 phosphorylation site, a sucrose non-fermenting-1 (SNF-1) homology domain, and a long C-terminal extension containing multiple potential protein kinase A phosphorylation sites. All three SIK family kinases are expressed broadly. SIK1 mRNA expression is regulated by multiple stimuli, including high dietary salt intake, ACTH signaling, glucagon signaling, excitable cell depolarization, and circadian rhythms. In contrast, SIK2 and SIK3 expression is constitutive in tissues in which these kinases are expressed. In humans, SIK2 and SIK3 are expressed ubiquitously, with highest SIK2 levels in adipose tissue and highest SIK3 expression in brain. Interestingly, SIK2 and SIK3 are closely linked on human chromosome 11 and mouse chromosome 9. A key role of SIKs is to control dynamic changes in phosphorylation and subcellular localization of class IIa HDACs and CRTC factors. Signals that increase intracellular cAMP levels lead to protein kinase A (PKA)-mediated SIK family member phosphorylation. PKA-mediated phosphorylation does not alter SIK intrinsic kinase activity. However, mutation of PKA phosphoacceptor sites leads to SIK variants whose cellular activity cannot be inhibited by cAMP-inducing signals. PKA-mediated SIK phosphorylation promotes interaction between SIK and 14–3–3 proteins. This PKA-inducible SIK/14–3–3 association leads to conformational changes and/or shifts in SIK cytoplasmic distribution which block the ability of these kinases to access and phosphorylate their substrates.

References

1.Wein MN,et al. Trends Endocrinol Metab. 2018 Oct; 29(10): 723–735.