ArticleThe FEBS journal2018
14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible kinases (SIKs).
Article in The FEBS journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 67 citations in OpenAlex.
- Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.Research square · 2026Article
- Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes.JCI insight · 2026Article
- Latest Advances in Obesity Treatment by Regulating Adipocyte Thermogenesis.PPAR research · 2026Review
- The Role of the Salt-inducible Kinases in the Endocrine Glands.Endocrinology · 2025Review
- Salt-inducible Kinase Regulation of Adipose Tissue Metabolism.Endocrinology · 2025Review
- The SIK3-N783Y mutation is associated with the human natural short sleep trait.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Regulation of Sleep Amount by CRTC1 via Transcription ofThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review).Oncology reports · 2024Review
- Understanding the roles of salt-inducible kinases in cardiometabolic disease.Frontiers in physiology · 2024Review
- Interruption of p38International journal of biological sciences · 2024Article
- 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
- Designing of potent anti-diabetic molecules by targeting SIK2 using computational approaches.Molecular diversity · 2023Article
- LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.Molecular cell · 2023Article
- A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.The Journal of clinical investigation · 2023Article
- The AMPK-like protein kinases Sik2 and Sik3 interact with Hipk and induce synergistic tumorigenesis in aFrontiers in cell and developmental biology · 2023Article
- Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods.Frontiers in pharmacology · 2023Article
- Quantitative phosphoproteomic analysis reveals unique cAMP signaling pools emanating from AC2 and AC6 in human airway smooth muscle cells.Frontiers in physiology · 2023Article
- Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib.Computational and structural biotechnology journal · 2022Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
The salt-inducible kinase (SIK) family regulates cellular gene expression via the phosphorylation of cAMP-regulated transcriptional coactivators (CRTCs) and class IIA histone deacetylases, which are sequestered in the cytoplasm by phosphorylation-dependent 14-3-3 interactions. SIK activity toward these substrates is inhibited by increases in cAMP signaling, although the underlying mechanism is unclear. Here, we show that the protein kinase A (PKA)-dependent phosphorylation of SIKs inhibits their catalytic activity by inducing 14-3-3 protein binding. SIK1 and SIK3 contain two functional PKA/14-3-3 sites, while SIK2 has four. In keeping with the dimeric nature of 14-3-3s, the presence of multiple binding sites within target proteins dramatically increases binding affinity. As a result, loss of a single 14-3-3-binding site in SIK1 and SIK3 abolished 14-3-3 association and rendered them insensitive to cAMP. In contrast, mutation of three sites in SIK2 was necessary to fully block cAMP regulation. Superimposed on the effects of PKA phosphorylation and 14-3-3 association, an evolutionary conserved domain in SIK1 and SIK2 (the so called RK-rich region; 595-624 in hSIK2) is also required for the inhibition of SIK2 activity. Collectively, these results point to a dual role for 14-3-3 proteins in repressing a family of Ser/Thr kinases as well as their substrates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.