Salt-Inducible Kinase Functions in Cellular Regulation and Metabolism

Salt-inducible kinases (SIK1, SIK2 and SIK3) comprise a subfamily of serine/threonine protein kinases within the AMPK-related kinase family that are activated by the master kinase LKB1 and inactivated by PKA-mediated phosphorylation. They serve as dynamic regulators of cellular energy balance by suppressing hepatic gluconeogenesis, modulating lipid synthesis and controlling glycogen turnover. Through reversible phosphorylation of CREB-regulated transcriptional co-activators (CRTCs) and class IIa histone deacetylases (HDAC4/5/7/9), SIKs govern transcriptional programmes underlying metabolic homeostasis, circadian rhythms and cell differentiation. Beyond the liver, SIK2 is enriched in adipose tissue where it influences insulin signalling, while SIK1 in the kidney forms a sodium-sensing triad with the Nax channel and Na+/K+-ATPase to mediate renal salt handling. In immune cells, SIK isoforms act as molecular switches that determine macrophage polarisation and cytokine output. Aberrant SIK activity has been implicated in metabolic diseases, salt-sensitive hypertension, inflammatory disorders and tumourigenesis, positioning SIKs as attractive targets for therapeutic intervention.

Research from Nature Portfolio

Seminal research has delineated the LKB1–SIK axis as a pivotal gluconeogenic gatekeeper in hepatocytes. Liver-specific ablation of LKB1 leads to hyperactivation of gluconeogenic genes and fasting hyperglycaemia, whereas pharmacological inhibition of SIKs promotes dephosphorylation of CRTCs and consequent upregulation of key enzymes in glucose production. Genetic reconstitution experiments confirm that SIK isoforms operate redundantly downstream of LKB1 to restrain gluconeogenesis, emphasising their central role in insulin-mediated suppression of hepatic glucose output.

Salt-Inducible Kinase Functions in Cellular Regulation and Metabolism publication trend

The graph below shows the total number of articles in salt-inducible kinase functions in cellular regulation and metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Salt-inducible kinase (SIK): A subgroup of LKB1-activated serine/threonine kinases within the AMPK-related family that regulate metabolic and transcriptional programmes in response to salt and hormonal cues.

AMPK family: Adenosine monophosphate-activated protein kinases and related kinases that sense cellular energy status and coordinate metabolic pathways.

Gluconeogenesis: The biosynthetic pathway by which glucose is generated from non-carbohydrate precursors, primarily in the liver.

CRTC (CREB-regulated transcriptional co-activator): A co-activator that, upon dephosphorylation, translocates to the nucleus to enhance CREB-dependent gene expression.

Histone deacetylase (HDAC): Enzymes that remove acetyl groups from histones, thereby modulating chromatin structure and transcriptional activity.

Macrophage polarisation: The process by which macrophages adopt pro-inflammatory or anti-inflammatory phenotypes in response to environmental signals.

Cytokine: A class of secreted proteins that mediate intercellular communication in immune and inflammatory responses.

Nax channel: A sodium-activated sodium channel that senses extracellular sodium concentration, particularly in the brain and kidney.

Na+/K+-ATPase: A membrane-bound enzyme complex that maintains cellular sodium and potassium gradients essential for cell volume, excitability and transport processes.

References

1. Deficiency of salt‐inducible kinase 2 (SIK2) promotes immune injury by inhibiting the maturation of lymphocytes. MedComm (2023).
2. Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases. Journal of Medicinal Chemistry (2024).
3. The Triad Na+ Activated Na+ Channel (Nax)—Salt Inducible KINASE (SIK) and (Na+ + K+)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension. International Journal of Molecular Sciences (2023).
4. Nuts and bolts of the salt-inducible kinases (SIKs). Biochemical Journal (2021).
5. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nature Communications (2014).
6. The Tumor Suppressor Kinase LKB1 Activates the Downstream Kinases SIK2 and SIK3 to Stimulate Nuclear Export of Class IIa Histone Deacetylases*. Journal of Biological Chemistry (2013).
7. Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. Biochemical Journal (2017).
8. Adipose-specific Expression, Phosphorylation of Ser794 in Insulin Receptor Substrate-1, and Activation in Diabetic Animals of Salt-inducible Kinase-2*. Journal of Biological Chemistry (2003).