ArticleThe Journal of biological chemistry2015
Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 55 citations in OpenAlex.
- PHKG2 confers resistance of ESCC to cisplatin and enhances CXCL8-dependent immunosuppression to exacerbate tumorigenesis.Cell death & disease · 2026Article
- The Role of the Salt-inducible Kinases in the Endocrine Glands.Endocrinology · 2025Review
- Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAMolecular neurobiology · 2024Article
- Understanding the roles of salt-inducible kinases in cardiometabolic disease.Frontiers in physiology · 2024Review
- Roles of salt‑inducible kinases in cancer (Review).International journal of oncology · 2023Review
- The multiple roles of salt-inducible kinases in regulating physiology.Physiological reviews · 2023Review
- LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma.Cancer discovery · 2023Article
- Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Nuts and bolts of the salt-inducible kinases (SIKs).The Biochemical journal · 2021Review
- SIKs suppress tumor function and regulate drug resistance in breast cancer.American journal of cancer research · 2021Article
- Lkb1 suppresses amino acid-driven gluconeogenesis in the liver.Nature communications · 2020Article
- Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway.Molecular metabolism · 2020Article
- The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis.Signal transduction and targeted therapy · 2020Review
- A salt-induced kinase is required for the metabolic regulation of sleep.PLoS biology · 2020Article
- The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.PLoS genetics · 2020Article
- Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks.Cell reports · 2019Article
- The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC.Cancer discovery · 2019Article
- Salt Inducible Kinase Signaling Networks: Implications for Acute Kidney Injury and Therapeutic Potential.International journal of molecular sciences · 2019Review
- Downregulated Salt-inducible Kinase 3 Expression Promotes Chemoresistance in Serous Ovarian Cancer via the ATP-binding Cassette Protein ABCG2.Journal of Cancer · 2019Article
- Parathyroid hormone(1-34) and its analogs differentially modulate osteoblasticThe Journal of biological chemistry · 2018Article
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Salt-inducible kinases (SIKs), members of the 5'-AMP-activated protein kinase (AMPK) family, are proposed to be important suppressors of gluconeogenic programs in the liver via the phosphorylation-dependent inactivation of the CREB-specific coactivator CRTC2. Although a dramatic phenotype for glucose metabolism has been found in SIK3-KO mice, additional complex phenotypes, dysregulation of bile acids, cholesterol, and fat homeostasis can render it difficult to discuss the hepatic functions of SIK3. The aim of this study was to examine the cell autonomous actions of SIK3 in hepatocytes. To eliminate systemic effects, we prepared primary hepatocytes and screened the small compounds suppressing SIK3 signaling cascades. SIK3-KO primary hepatocytes produced glucose more quickly after treatment with the cAMP agonist forskolin than the WT hepatocytes, which was accompanied by enhanced gluconeogenic gene expression and CRTC2 dephosphorylation. Reporter-based screening identified pterosin B as a SIK3 signaling-specific inhibitor. Pterosin B suppressed SIK3 downstream cascades by up-regulating the phosphorylation levels in the SIK3 C-terminal regulatory domain. When pterosin B promoted glucose production by up-regulating gluconeogenic gene expression in mouse hepatoma AML-12 cells, it decreased the glycogen content and stimulated an association between the glycogen phosphorylase kinase gamma subunit (PHKG2) and SIK3. PHKG2 phosphorylated the peptides with sequences of the C-terminal domain of SIK3. Here we found that the levels of active AMPK were higher both in the SIK3-KO hepatocytes and in pterosin B-treated AML-12 cells than in their controls. These results suggest that SIK3, rather than SIK1, SIK2, or AMPKs, acts as the predominant suppressor in gluconeogenic gene expression in the hepatocytes.
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