Affinage

SIK1

Serine/threonine-protein kinase SIK1 · UniProt P57059

Length
783 aa
Mass
84.9 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIK1 is an LKB1-activated, AMPK-family serine/threonine kinase that integrates cAMP, calcium, and energy signals to control gene transcription, metabolism, and cell fate, functioning broadly as a tumor-suppressive node (PMID:19622832, PMID:31350328). Its activation requires LKB1-mediated phosphorylation at Thr182 followed by Ser186 autophosphorylation, with sustained activity dependent on sequential GSK-3β phosphorylation (PMID:18946175); in distinct contexts calcium/calmodulin-dependent kinase activates SIK1 at Thr322 (PMID:17939993), and PKA phosphorylation at Thr475 within a PEST domain stabilizes the protein against proteasomal degradation (PMID:23256157). A core transcriptional output of SIK1 is phosphorylation of CRTC/TORC coactivators (CRTC1 at multiple sites, CRTC2 at Ser171), driving their cytoplasmic sequestration or RFWD2-mediated degradation to repress CREB-dependent gluconeogenic and steroidogenic gene programs (PMID:33013689, PMID:29408765, PMID:25662274); SIK1 reinforces this by activating PDE4 to lower cAMP (PMID:32599076). SIK1 also phosphorylates class II HDACs (HDAC4/HDAC5) to drive their 14-3-3-dependent nuclear export and MEF2 activation, coupling cAMP/PKA signaling to myogenic differentiation (PMID:18946175, PMID:23256157, PMID:25384047). SIK1 participates in a CREB-driven negative feedback loop that limits light-induced circadian phase shifts in the SCN through CRTC1 deactivation (PMID:23993098). Beyond transcription, SIK1 phosphorylates PME-1 to activate Na+,K+-ATPase upon sodium/calcium sensing (PMID:17939993), phosphorylates MCM2 after recruitment by the GINS subunit Sld5 to license DNA replication (PMID:27592030), phosphorylates SMRT at Thr1391 to inhibit Wnt/β-catenin signaling (PMID:26778753), and phosphorylates SR-B1 at Ser496 to promote HDL-cholesterol uptake (PMID:26567857). SIK1 is opposed by AKT, which phosphorylates it to promote 14-3-3 binding, cytoplasmic translocation, and Pin1/ITCH-dependent ubiquitination and degradation (PMID:36806887), by the E3 ligase RNF2 (PMID:27911266), and by BMI1/RING1B-mediated epigenetic silencing of its promoter (PMID:35346195). De novo C-terminal SIK1 mutations that escape degradation and alter nuclear localization cause developmental epilepsy and autism-spectrum phenotypes (PMID:25839329, PMID:34295222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2004 Low

    Initial characterization asked where SIK1 acts and what cellular process it influences, establishing an early link to cell cycle control.

    Evidence Inducible SIK1 kinase domain expression in CHO cells with flow cytometric DNA content analysis

    PMID:15177563

    Open questions at the time
    • Single overexpression in a heterologous line with no substrate identified
    • Does not establish a physiological cell-cycle role
    • Mechanism of the polyploidy phenotype undefined
  2. 2007 High

    Established SIK1 as a class II HDAC kinase downstream of CREB, defining the HDAC5-MEF2 transcriptional axis in muscle.

    Evidence Dominant-negative CREB mice, viral SIK1 re-expression, and HDAC antagonist rescue of dystrophic phenotype

    PMID:17468767

    Open questions at the time
    • Activation inputs not fully resolved at this stage
    • HDAC5 site specificity not mapped here
  3. 2007 High

    Defined a calcium-triggered activation route and a non-transcriptional substrate, showing SIK1 couples sodium sensing to ion-pump regulation.

    Evidence Co-IP, in vitro kinase assays, and intracellular Ca2+/Na+ measurements on the Na+,K+-ATPase complex

    PMID:17939993

    Open questions at the time
    • Physiological contexts beyond cultured cells not defined
    • Interplay with the LKB1 activation route unresolved
  4. 2008 High

    Resolved the activation hierarchy of SIK1, placing LKB1-Thr182, Ser186 autophosphorylation, and GSK-3β in a defined sequence.

    Evidence In vitro kinase assays with purified GSK-3β plus inhibitor and nuclear-export readouts in C2C12

    PMID:18946175

    Open questions at the time
    • Quantitative contribution of each phospho-event to activity unclear
    • Tissue-specificity of GSK-3β input untested
  5. 2009 High

    Placed SIK1 in the LKB1 tumor-suppressor pathway, linking it to p53-dependent anoikis and metastasis suppression.

    Evidence Kinome-wide RNAi screen, in vivo metastasis model, and combinatorial-knockdown epistasis

    PMID:19622832

    Open questions at the time
    • Direct SIK1 substrate connecting to p53 not identified
    • Generality across tumor types not established
  6. 2010 Medium

    Implicated SIK1 in developmental cell-cycle exit, showing it controls a p57Kip2 network during cardiomyogenesis.

    Evidence Gene-trap SIK1-null ES cells, embryoid body differentiation, and expression profiling

    PMID:20140255

    Open questions at the time
    • Direct substrate linking SIK1 to p57Kip2 not defined
    • In vivo developmental requirement not tested
  7. 2011 Medium

    Demonstrated stimulus-coupled SIK1 activation in vivo, with cocaine driving Thr182 phosphorylation, nuclear import, and HDAC5/CRTC shuttling.

    Evidence In vivo rat cocaine treatment with phospho-SIK1 immunostaining, fractionation, and MEF2C readouts

    PMID:21954104

    Open questions at the time
    • Upstream kinase driving Thr182 in this context not pinned down
    • Behavioral consequences not tested
  8. 2012 High

    Explained how cAMP/PKA stabilizes SIK1, identifying Thr475 in a PEST domain as the degradation-protective PKA site coupling SIK1 to myogenesis.

    Evidence Cell-free PKA assay, proteasome inhibition, PEST mutagenesis, and knockdown in myogenic progenitors

    PMID:23256157

    Open questions at the time
    • Identity of the degrading E3 ligase not addressed here
    • Stoichiometry of stabilization not quantified
  9. 2013 High

    Defined SIK1 as a circadian feedback brake, with CREB-induced SIK1 deactivating CRTC1 to limit light-induced phase shifts.

    Evidence Light-regulated SCN transcriptomics, in vivo SCN Sik1 knockdown, and behavioral phase-shift assays

    PMID:23993098

    Open questions at the time
    • Molecular timing of the feedback loop not fully kinetically resolved
    • Relevance to peripheral clocks untested
  10. 2013 Medium

    Mapped the CRTC2 phosphorylation site (Ser171) underlying SIK1 suppression of hepatic gluconeogenic transcription.

    Evidence SIK1 overexpression/knockdown in hepatocytes with phospho-CRTC2 blotting and gluconeogenic reporters

    PMID:33013689

    Open questions at the time
    • Single-lab methods
    • In vivo glycemic relevance not directly tested here
  11. 2014 Medium

    Connected receptor signaling to SIK1, showing gastrin via CCK2/Gq induces and activates SIK1 to drive HDAC4 export and restrain cancer cell migration.

    Evidence siRNA knockdown, phospho-HDAC4 blotting, HDAC export and migration assays in gastric cells

    PMID:25384047

    Open questions at the time
    • Direct HDAC4 site not mapped
    • ICER regulatory loop only partially defined
  12. 2015 High

    Expanded the SIK1 substrate repertoire and tumor-suppressor scope: SMRT-Thr1391 phosphorylation inhibits Wnt/β-catenin, SR-B1-Ser496 promotes cholesterol uptake, and CRTC2 mediates steroidogenic feedback.

    Evidence In vitro kinase assays, Co-IP, mutant rescue, reporter/ChIP, xenografts, and cholesterol uptake/FISH assays

    PMID:25662274 PMID:26567857 PMID:26778753

    Open questions at the time
    • Cross-talk between these substrate arms not integrated
    • Tissue-selectivity of substrate choice unexplained
  13. 2015 Medium

    Linked SIK1 to human disease, identifying de novo C-terminal mutations causing developmental epilepsy with retained kinase activity but altered stability and localization.

    Evidence In vitro kinase/autophosphorylation assays, localization imaging, and human neuropathology

    PMID:25839329

    Open questions at the time
    • Causal neuronal mechanism not resolved in this study
    • Genotype-phenotype range incomplete
  14. 2015 Medium

    Established a cardiovascular role, with SIK1 restraining TGF-β1 signaling and VSMC contractile phenotype under salt stress.

    Evidence SIK1 knockout mice on high-salt diet with in vitro VSMC/fibroblast knockdown and blood pressure monitoring

    PMID:25556206

    Open questions at the time
    • Direct substrate in TGF-β1 pathway not identified
    • Single-lab model
  15. 2016 Medium

    Revealed a replication-licensing function, with Sld5-mediated recruitment enabling SIK1 phosphorylation of MCM2 to activate the helicase.

    Evidence Co-IP, in vitro MCM2 kinase assay, and SIK1 knockdown replication assays

    PMID:27592030

    Open questions at the time
    • How SIK1 activity is timed to S phase unclear
    • Independent confirmation of MCM2 site needed
  16. 2017 Medium

    Identified RNF2 as an E3 ligase degrading SIK1 in hepatocellular carcinoma, defining a route of tumor-promoting SIK1 loss.

    Evidence Co-IP, RNF2 knockdown rescue, and xenograft models

    PMID:27911266

    Open questions at the time
    • Degron and ubiquitination sites on SIK1 not mapped
    • Single-lab Co-IP evidence
  17. 2018 Medium

    Distinguished SIK1 from paralogs in metabolic control, showing SIK1-specific induction of CRTC1 phosphorylation and RFWD2-mediated degradation to repress gluconeogenesis.

    Evidence SIK1/2/3 comparison, CRTC1 phosphomutant analysis, ubiquitination assays, and RFWD2 co-expression

    PMID:29408765

    Open questions at the time
    • In vivo relevance of CRTC1 degradation untested here
    • Why only SIK1 acts on CRTC1 unexplained
  18. 2018 Medium

    Extended SIK1's anti-inflammatory and pro-survival role, showing it suppresses NF-κB and apoptosis in microglia.

    Evidence SIK1 knockdown, NF-κB reporter, TUNEL/caspase assays, and p65-depletion epistasis

    PMID:29929190

    Open questions at the time
    • Direct SIK1 substrate in NF-κB pathway not identified
    • Tier 3 single-lab evidence
  19. 2019 High

    Confirmed in vivo that SIK1 (with SIK3) mediates LKB1 tumor suppression in lung cancer through CRTC2-dependent AP1/IL6 signaling.

    Evidence CRISPR deletion, conditional Sik1 knockout Kras lung cancer mice, and CRTC2 epistasis

    PMID:31350328

    Open questions at the time
    • Relative contributions of SIK1 versus SIK3 not fully separated
    • Therapeutic implications of restoring SIK activity not addressed
  20. 2020 High

    Added effector and physiological dimensions: SIK1 activates PDE4 to lower cAMP and suppress gluconeogenesis, and PKA-Ser577 phosphorylation links SIK1 to sleep-need regulation.

    Evidence siRNA/overexpression with PDE4 activity and cAMP assays in hepatocytes/ob-ob mice; Sik1-S577A knock-in mice with polysomnography

    PMID:32457359 PMID:32599076

    Open questions at the time
    • Mechanism by which SIK1 activates PDE4 not detailed
    • Neural circuit mediating the sleep effect undefined
  21. 2021 Medium

    Mechanistically connected SIK1 C-terminal truncations to neuronal dysfunction, showing mislocalization and disrupted excitatory/inhibitory balance with autism-like behavior.

    Evidence CRISPR truncation knock-in mice, localization imaging, electrophysiology, and behavioral assays

    PMID:34295222

    Open questions at the time
    • Causal substrate driving the synaptic phenotype not identified
    • Single-lab model
  22. 2023 High

    Defined the dominant negative-regulatory axis: AKT phosphorylates SIK1 to recruit 14-3-3, drive cytoplasmic translocation, and trigger Pin1/ITCH-dependent degradation, relieving SIK1 repression of STAT3.

    Evidence MS interactome, reciprocal Co-IPs, fractionation, phosphorylation, and ubiquitination assays

    PMID:36806887

    Open questions at the time
    • AKT phosphosite(s) on SIK1 not specified here
    • Reconciliation with PKA-stabilization not addressed
  23. 2023 Medium

    Added a TGF-β axis to SIK1's tumor-suppressive repertoire via Smad7 interaction and inhibition of Smad2 phosphorylation in colorectal cancer.

    Evidence Single Co-IP (SIK1-Smad7), phospho-Smad2 blotting, and galunisertib rescue

    PMID:37670972

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Whether SIK1 directly phosphorylates a Smad component unknown
  24. 2022 Medium

    Revealed epigenetic suppression of SIK1, with BMI1/RING1B repressing its promoter via H2AK119ub and H3K4me3 loss in osteosarcoma.

    Evidence ChIP-qPCR at the SIK1 promoter, SIK1 rescue in BMI1-deficient cells, and xenografts

    PMID:35346195

    Open questions at the time
    • Upstream signals controlling BMI1 recruitment unknown
    • Single-lab evidence
  25. 2024 Medium

    Showed post-transcriptional control of SIK1, with FTO-mediated m6A demethylation reducing SIK1 mRNA stability and impairing trophoblast syncytialization in diabetes.

    Evidence MeRIP-Seq/RNA-Seq, FTO binding to the SIK1 3'-UTR, mRNA stability and syncytialization assays

    PMID:38883837

    Open questions at the time
    • Downstream SIK1 substrate in syncytialization not defined
    • Single-lab evidence
  26. 2025 High

    Identified a context-specific oncogenic output, with SIK1 phosphorylating HDAC5-Ser498 to stabilize it via 14-3-3, deacetylate STAT6, and confer ferroptosis resistance through SLC7A11.

    Evidence In vitro kinase assay, Co-IP, ubiquitination and STAT6 acetylation assays, organoid and PDX models

    PMID:40250791

    Open questions at the time
    • Reconciliation of this oncogenic role with SIK1 tumor suppression unresolved
    • Tissue determinants of pro- versus anti-tumor output unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SIK1 substrate selection and its dual tumor-suppressive versus oncogenic outputs are determined across tissues, and how competing PKA-stabilizing and AKT-destabilizing inputs are integrated in vivo.
  • No unified model of context-dependent substrate choice
  • Integration of opposing stability inputs untested in vivo
  • Structural basis of substrate recognition undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 7 GO:0140110 transcription regulator activity 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-69306 DNA Replication 1 R-HSA-9909396 Circadian clock 1
Partners
CRTC1CRTC2HDAC5ITCHLKB1RNF2SLD5SMAD7
Complex memberships
Na+,K+-ATPase regulatory complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SIK1 functions as a class II HDAC kinase: CREB transcriptionally induces SIK1 expression, and SIK1 phosphorylates class II HDACs (e.g., HDAC5), leading to their inactivation and promotion of MEF2 activity in skeletal myocytes. Loss of SIK1 in M-ACREB mice reduced class II HDAC phosphorylation and caused a dystrophic phenotype. Dominant-negative CREB transgenic mice (M-ACREB), viral re-expression of SIK1, small molecule HDAC antagonist rescue of dystrophic phenotype Nature medicine High 17468767
2007 SIK1 constitutively associates with the Na+,K+-ATPase (NK) regulatory complex. Elevated intracellular Na+ triggers Ca2+ influx via Na+/Ca2+ exchanger, activating SIK1 at Thr-322 via a calcium calmodulin-dependent kinase. Activated SIK1 phosphorylates PME-1, causing its dissociation from a PP2A/PME-1 complex on the NK alpha-subunit, leading to NK alpha-subunit dephosphorylation and increased Na+,K+-ATPase catalytic activity. Co-immunoprecipitation, in vitro phosphorylation assays, intracellular Ca2+ and Na+ measurements, fractionation Proceedings of the National Academy of Sciences of the United States of America High 17939993
2008 SIK1 is activated by LKB1, which phosphorylates SIK1 at Thr182. SIK1 then auto-phosphorylates Ser186 (at the +4 position), and sustained SIK1 activity requires sequential phosphorylation of Ser186 then Thr182 by GSK-3β. Activated SIK1 phosphorylates TORC (CRTC) coactivators to repress CREB-dependent transcription, and also phosphorylates HDAC5 to promote nuclear export and MEF2C-driven PGC-1α expression in C2C12 myoblasts. In vitro kinase assays with purified GSK-3β, overexpression and inhibitor studies (GSK-3β and SIK inhibitors), AICAR treatment, nuclear export assays Endocrine journal High 18946175
2009 SIK1 acts downstream of LKB1 and upstream of p53 in an anoikis pathway. SIK1 loss compromised p53 function upon cell detachment, enabling anchorage-independent growth and metastasis in vivo. LKB1 required functional SIK1 to promote p53-dependent anoikis and suppress invasion. Kinome-wide RNAi loss-of-function screen, in vivo mouse metastasis model, Matrigel invasion assay, epistasis by combinatorial knockdown Science signaling High 19622832
2012 SIK1 protein stability is regulated by PKA-mediated phosphorylation at Thr475 within a PEST domain: PKA phosphorylation at Thr475 extends SIK1 half-life by protecting it from proteasomal degradation. During myogenic differentiation, elevated PKA activity leads to SIK1 accumulation and stabilization, coupling cAMP signaling to the HDAC-MEF2 pathway. Depletion of SIK1 in primary muscle precursors impairs MEF2 protein accumulation and myogenic differentiation. Cell-free PKA phosphorylation assay, proteasome inhibitor treatment, PEST domain mutant analysis, SIK1 knockdown in primary myogenic progenitors Proceedings of the National Academy of Sciences of the United States of America High 23256157
2013 SIK1 is part of a negative feedback loop in circadian clock entrainment in the SCN. Light-induced CRTC1 coactivates CREB, driving Per1 and Sik1 expression. Induced SIK1 then phosphorylates and deactivates CRTC1, suppressing further clock shifts. SCN-specific Sik1 knockdown increases behavioral phase shifts and accelerates re-entrainment after experimental jet lag. Light-regulated SCN transcriptomics, in vivo Sik1 knockdown in SCN, behavioral phase-shift assays in mice Cell High 23993098
2013 SIK1 phosphorylates CRTC2 (TORC2) at Ser171, causing its cytoplasmic sequestration, which suppresses gluconeogenic gene transcription (PEPCK, G6Pase) by preventing CRTC2-CREB coactivation in hepatic cells. SIK1 overexpression and knockdown in hepatocytes, phospho-CRTC2 immunoblotting, gluconeogenic reporter assays Frontiers in endocrinology Medium 33013689
2011 Cocaine acutely activates SIK1 by phosphorylation at Thr-182, accompanied by nuclear import of SIK1. Nuclear SIK1 then phosphorylates HDAC5, causing shuttling of phospho-HDAC5 from nucleus to cytoplasm of striatal cells, leading to MEF2C induction. SIK1 activation also causes nuclear-to-cytoplasm translocation of TORC1/3. In vivo rat cocaine treatment, phospho-Thr182-SIK1 immunostaining, subcellular fractionation, HDAC5 phosphorylation assays, MEF2C gene expression analysis Synapse (New York, N.Y.) Medium 21954104
2015 De novo SIK1 mutations outside the kinase domain cause developmental epilepsies. Mutant SIK1 proteins retain autophosphorylation and kinase activity toward HDAC5, but truncated forms are resistant to degradation and show altered subcellular localization compared to wild-type SIK1. In vitro kinase assays (autophosphorylation and HDAC5 substrate), subcellular localization imaging, neuropathological examination of human SIK1 mutation cases American journal of human genetics Medium 25839329
2015 SIK1 phosphorylates the co-repressor SMRT at Thr1391, which promotes SMRT/NCoR association with TBL1/TBLR1 and disrupts β-catenin's binding to the TBL1/TBLR1 complex, thereby inhibiting Wnt/β-catenin transcriptional activity in HCC. A non-phosphorylatable SMRT-T1391A mutant reverses this effect. Immunoprecipitation, in vitro kinase assay, luciferase reporter assay, chromatin immunoprecipitation, xenograft tumor models, SMRT-T1391A rescue experiments Journal of hepatology High 26778753
2015 SIK1 physically interacts with and phosphorylates the C-terminal cytoplasmic domain of SR-B1 (scavenger receptor class B type 1), specifically at Ser496. This phosphorylation is critical for SIK1 stimulation of selective HDL-cholesteryl ester (CE) uptake and SR-B1-mediated steroidogenesis in adrenal cells. Both intact SIK1 catalytic activity and PKA-mediated phosphorylation of SIK1 are required for this effect. Co-immunoprecipitation, in vitro kinase assay, Ser496 mutagenesis, HDL-BODIPY-CE uptake assay, SIK1 knockdown/overexpression in adrenal cells Biochemistry High 26567857
2015 SIK1 expression is regulated by and inhibited by cAMP signaling via induction of CRTC2: SIK1 represses StAR transcription/splicing through phosphorylation of CRTC2, but only as cAMP levels decline, providing negative feedback on steroidogenic gene expression in adrenal/testis cells. FISH-based single-cell visualization of StAR pRNA and mRNA, SIK1 overexpression/knockdown in Y1 adrenal and MA10 testis cells, qPCR Molecular and cellular endocrinology Medium 25662274
2016 SIK1 is recruited to DNA replication sites via interaction with the GINS complex component Sld5. SIK1 phosphorylates MCM2 at five conserved N-terminal residues, which is essential for MCM helicase activation. SIK1 depletion causes defective DNA replication. Co-immunoprecipitation (Sld5-SIK1 interaction), in vitro kinase assay (MCM2 phosphorylation), SIK1 knockdown DNA replication assays Cellular signalling Medium 27592030
2017 RNF2 acts as an E3 ubiquitin ligase that directly interacts with SIK1 and targets it for proteasomal degradation in hepatocellular carcinoma. Downregulation of RNF2 restores SIK1 levels and inhibits HCC cell growth. Co-immunoprecipitation, RNF2 knockdown rescue experiments, xenograft tumor models Oncotarget Medium 27911266
2018 SIK1 suppresses NF-κB signaling in microglia: SIK1 knockdown promotes alcohol-induced NF-κB activity and increases caspase-3/9-mediated apoptosis in microglia, whereas SIK1 expression reduces NF-κB signaling. NF-κB inhibition (p65 depletion) reverses SIK1 knockdown-mediated apoptosis. SIK1 knockdown, NF-κB luciferase reporter assay, TUNEL staining, caspase activity assays, cell fluorescence staining Cellular physiology and biochemistry Medium 29929190
2019 SIK1 and SIK3 are critical downstream effectors of LKB1 tumor suppressor function in NSCLC. Conditional genetic loss of Sik1 increased tumor growth in Kras-driven lung cancer mouse models, enhanced by Sik3 co-deletion. The SIK substrate CRTC2 was required for the proliferative benefit of SIK loss and for upregulation of AP1 and IL6 signaling. CRISPR-based genetic deletion in cell lines, conditional Sik1 knockout mouse models of Kras lung cancer, gene-expression analysis, CRTC2 epistasis experiments Cancer discovery High 31350328
2020 SIK1 phosphorylation at Ser577 (a PKA site) negatively regulates sleep: mice with Sik1-S577A mutation (loss of PKA phosphorylation site) showed shorter wake time, longer NREM sleep, and higher NREM delta density, indicating PKA-SIK1 signaling is involved in sleep need regulation. Sik1S577A knock-in mice generated by genome editing, polysomnographic sleep recording, sleep deprivation experiments Scientific reports Medium 32457359
2020 SIK1 activates PDE4, leading to reduced cAMP accumulation and inhibition of the cAMP/PKA/CREB pathway, thereby suppressing hepatic gluconeogenesis. The natural compound phanginin A activates SIK1 via LKB1 phosphorylation, and its effects are blocked by SIK1 knockdown or pan-SIK inhibitor HG-9-91-01. SIK1 siRNA knockdown, SIK1 overexpression, PDE4 activity assays, cAMP measurement, gluconeogenic gene expression, pan-SIK inhibitor HG-9-91-01, ob/ob mouse glucose tolerance assays Molecular metabolism High 32599076
2021 C-terminal truncation mutations of SIK1 (as in ASD/epilepsy patients) alter SIK1 subcellular distribution from exclusively nuclear to both nuclear and cytoplasmic. SIK1-MT mice show increased excitatory synaptic transmission, enhanced pyramidal neuron excitability in mPFC layer 5, disrupted E/I synaptic balance, and increased repetitive behavior. CRISPR/Cas9-generated SIK1 truncation knock-in mice, subcellular localization imaging, electrophysiology (excitatory and inhibitory synaptic recordings), behavioral assays Frontiers in molecular neuroscience Medium 34295222
2022 BMI1 directly binds the SIK1 promoter in a complex with RING1B, promoting H2AK119 monoubiquitination and inhibiting H3K4me3, resulting in transcriptional repression of SIK1 in osteosarcoma cells. ChIP-qPCR at SIK1 promoter for BMI1, RING1B, H2AK119ub, and H3K4me3; SIK1 rescue experiments in BMI1-deficient cells; xenograft models Cancer cell international Medium 35346195
2023 AKT binds SIK1 and phosphorylates it, relieving SIK1-mediated repression of STAT3 in a phosphorylation-dependent manner. AKT-phosphorylated SIK1 interacts with 14-3-3, translocates to the cytoplasm, and is then facilitated by the isomerase Pin1 to interact with E3 ligase ITCH, leading to SIK1 ubiquitination and degradation. Mass spectrometry-based interactome analysis, Co-immunoprecipitation (AKT-SIK1, SIK1-14-3-3, SIK1-Pin1, SIK1-ITCH), subcellular fractionation, phosphorylation assays, ubiquitination assays Cancer research High 36806887
2023 SIK1 interacts with Smad7 (validated by co-immunoprecipitation) and inhibits phosphorylation of Smad2, suppressing TGF-β/Smad signaling and downstream EMT markers in colorectal cancer cells. Co-immunoprecipitation (SIK1-Smad7), phospho-Smad2 immunoblotting, SIK1 overexpression/knockdown, galunisertib (TGF-β inhibitor) rescue Journal of Cancer Medium 37670972
2018 SIK1 suppresses gluconeogenic gene transcription by inducing phosphorylation, K48-linked polyubiquitination and proteasomal degradation of CRTC1. Phosphorylation occurs at S155, S167, S188 and S346 of CRTC1. This ubiquitination is mediated by the E3 ligase RFWD2. SIK2 and SIK3 do not replicate this effect on CRTC1. SIK1/2/3 overexpression comparison, CRTC1 phosphomutant analysis, ubiquitination assays, RFWD2 co-expression, gluconeogenic gene reporter assays Biochimica et biophysica acta. Gene regulatory mechanisms Medium 29408765
2010 Lack of SIK1 in mouse embryonic stem cells impairs cardiomyogenesis: in SIK1-null ES-derived embryoid bodies, temporal appearance of cardiomyocytes is delayed. Expression profiling revealed SIK1 controls a genetic network involving the cyclin-dependent kinase inhibitor p57(Kip2) to regulate cardiomyoblast cell cycle exit. Gene-trap SIK1-null ES cells, embryoid body differentiation assay, gene expression profiling PloS one Medium 20140255
2015 SIK1 knockout mice on a chronic high-salt diet develop increased systolic blood pressure, upregulated TGF-β1 signaling, increased endothelin-1, and vascular smooth muscle cell contractile marker expression. SIK1 knockdown in vitro upregulates collagen in adventitial fibroblasts and contractile markers in VSMCs, establishing SIK1 as a regulator of VSMC phenotype via TGF-β1 inhibition. SIK1 knockout mice with high-salt challenge, SIK1 in vitro knockdown in VSMCs and fibroblasts, blood pressure monitoring, TGF-β1 signaling assays Circulation research Medium 25556206
2014 Gastrin induces SIK1 expression through Gq/G11-coupled CCK2 receptor signaling, and SIK1 induction is negatively regulated by ICER. Gastrin activates LKB1 at Ser-428 and SIK1 at Thr-182. Ectopic SIK1 increases gastrin-induced HDAC4 phosphorylation and nuclear export of HDACs. SIK1 knockdown increases migration of gastric adenocarcinoma cells. SIK1 siRNA knockdown, phospho-HDAC4 immunoblotting, HDAC nuclear export assay, luciferase reporter assays, migration assay PloS one Medium 25384047
2025 SIK1 phosphorylates HDAC5 at Ser498, promoting HDAC5 interaction with 14-3-3 protein, which protects HDAC5 from TRIM28-mediated ubiquitylation and degradation. SIK1-stabilized HDAC5 deacetylates STAT6, enhancing its transcriptional activity to upregulate SLC7A11 expression, rendering pancreatic cancer cells resistant to ferroptosis. In vitro kinase assay (HDAC5 Ser498 phosphorylation), Co-immunoprecipitation (HDAC5-14-3-3, HDAC5-TRIM28), ubiquitination assay, STAT6 acetylation assays, organoid and PDX models Cancer letters High 40250791
2024 FTO-mediated m6A demethylation at the 3'-UTR of SIK1 mRNA reduces SIK1 expression and mRNA stability in trophoblasts under hyperglycemic conditions. Decreased SIK1 impairs placental cytotrophoblast syncytialization in type 2 diabetes mellitus. MeRIP-Seq and RNA-Seq combined analysis, FTO binding to SIK1 3'-UTR m6A site, mRNA stability assays, trophoblast syncytialization functional assays iScience Medium 38883837
2004 SIK1 (snf1lk/msk) is expressed in skeletal muscle progenitor cells and early cardiomyocytes. Inducible expression of the SIK1 kinase domain in CHO cells blocks cell division and causes extra rounds of DNA replication to yield 8N and 16N cells, suggesting a role in G2/M cell cycle regulation. Tetracycline-inducible SNF1LK kinase domain expression in CHO cells, flow cytometric DNA content analysis Genomics Low 15177563

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. The Journal of molecular diagnostics : JMD 1858 25801821
2007 SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature medicine 234 17468767
2021 Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01. Cell stem cell 192 33545080
2006 Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Molecular cell 187 17081988
2013 The CRTC1-SIK1 pathway regulates entrainment of the circadian clock. Cell 177 23993098
2010 Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Molecular cell 151 20864036
2021 Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. Nature cancer 139 34308366
2009 SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Science signaling 135 19622832
2021 Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS. Nature communications 134 34145282
2017 Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC medical genomics 134 28526081
2008 MSK activation and physiological roles. Frontiers in bioscience : a journal and virtual library 130 18508628
2016 Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways. BMJ open 129 27496243
2019 The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC. Cancer discovery 121 31350328
2018 The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants. Cell host & microbe 121 30212650
2015 Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway. Molecular cancer 89 25890196
2007 SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process. Proceedings of the National Academy of Sciences of the United States of America 82 17939993
2016 Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation. Journal of hepatology 77 26778753
2015 Ovarian clear cell carcinoma, outcomes by stage: the MSK experience. Gynecologic oncology 75 26404183
2008 Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1. Nucleic acids research 75 18334532
2010 Down-regulation of IL-6 production by astaxanthin via ERK-, MSK-, and NF-κB-mediated signals in activated microglia. International immunopharmacology 70 20932499
2022 Circular RNA EIF4G3 suppresses gastric cancer progression through inhibition of β-catenin by promoting δ-catenin ubiquitin degradation and upregulating SIK1. Molecular cancer 65 35780119
1992 Characterization of murine hemopoietic-supportive (MS-1 and MS-5) and non-supportive (MS-K) cell lines. Leukemia 62 1375698
2016 Attenuated LKB1-SIK1 signaling promotes epithelial-mesenchymal transition and radioresistance of non-small cell lung cancer cells. Chinese journal of cancer 55 27266881
2012 Characterization of the cellular action of the MSK inhibitor SB-747651A. The Biochemical journal 55 21970321
2015 De novo mutations in SIK1 cause a spectrum of developmental epilepsies. American journal of human genetics 49 25839329
2008 Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts. Endocrine journal 48 18946175
2009 SIK1/SOS2 networks: decoding sodium signals via calcium-responsive protein kinase pathways. Pflugers Archiv : European journal of physiology 45 19247687
2015 Increased arterial blood pressure and vascular remodeling in mice lacking salt-inducible kinase 1 (SIK1). Circulation research 43 25556206
2015 miR-203 promotes proliferation, migration and invasion by degrading SIK1 in pancreatic cancer. Oncology reports 43 26719072
2020 Exosomal miR-130b-3p targets SIK1 to inhibit medulloblastoma tumorigenesis. Cell death & disease 39 32483145
2010 Intracellular sodium sensing: SIK1 network, hormone action and high blood pressure. Biochimica et biophysica acta 39 20347966
2012 Regulation of SIK1 abundance and stability is critical for myogenesis. Proceedings of the National Academy of Sciences of the United States of America 37 23256157
2021 Expanding the spectrum of thyroid carcinoma with somatic DICER1 mutation: a survey of 829 thyroid carcinomas using MSK-IMPACT next-generation sequencing platform. Virchows Archiv : an international journal of pathology 36 34580763
2013 CALHM1 controls the Ca²⁺-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. Journal of cell science 36 23345406
2011 Cocaine induces the expression of MEF2C transcription factor in rat striatum through activation of SIK1 and phosphorylation of the histone deacetylase HDAC5. Synapse (New York, N.Y.) 36 21954104
2019 MicroRNA-17 promotes cell proliferation and migration in human colorectal cancer by downregulating SIK1. Cancer management and research 35 31118777
2022 BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1. Cancer cell international 34 35346195
2023 AKT Blocks SIK1-Mediated Repression of STAT3 to Promote Breast Tumorigenesis. Cancer research 32 36806887
2017 Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis. Oncotarget 32 27911266
2020 Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need. Scientific reports 31 32457359
2020 Purification and characterization of a novel white highly thermo stable laccase from a novel Bacillus sp. MSK-01 having potential to be used as anticancer agent. International journal of biological macromolecules 31 33340630
2021 Distinctive role of SIK1 and SIK3 isoforms in aerobic glycolysis and cell growth of breast cancer through the regulation of p53 and mTOR signaling pathways. Biochimica et biophysica acta. Molecular cell research 30 33545220
2020 Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway. Molecular metabolism 29 32599076
2016 Suppression of SIK1 by miR-141 in human ovarian cancer cell lines and tissues. International journal of molecular medicine 29 27081781
2005 (1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: a novel class of potent MSK-1-inhibitors. Bioorganic & medicinal chemistry letters 29 15950465
1993 The MsK family of alfalfa protein kinase genes encodes homologues of shaggy/glycogen synthase kinase-3 and shows differential expression patterns in plant organs and development. The Plant journal : for cell and molecular biology 28 8401615
2020 Gut microbiota modulation by both Lactobacillus fermentum MSK 408 and ketogenic diet in a murine model of pentylenetetrazole-induced acute seizure. Epilepsy research 27 33276243
2009 H89, an inhibitor of PKA and MSK, inhibits cyclic-AMP response element binding protein-mediated MAPK phosphatase-1 induction by lipopolysaccharide. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 26 19547917
2007 MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcription. European journal of immunology 26 17668895
2015 Stimulation of StAR expression by cAMP is controlled by inhibition of highly inducible SIK1 via CRTC2, a co-activator of CREB. Molecular and cellular endocrinology 23 25662274
2019 Response surface based optimization of laccase production from Bacillus sp. MSK-01 using fruit juice waste as an effective substrate. Heliyon 21 31193314
2018 SIK1-LNC represses the proliferative, migrative, and invasive abilities of lung cancer cells. OncoTargets and therapy 21 30050311
2015 A Novel Role of Salt-Inducible Kinase 1 (SIK1) in the Post-Translational Regulation of Scavenger Receptor Class B Type 1 Activity. Biochemistry 21 26567857
2014 Salt-inducible kinase 1 (SIK1) is induced by gastrin and inhibits migration of gastric adenocarcinoma cells. PloS one 21 25384047
2010 Lack of sik1 in mouse embryonic stem cells impairs cardiomyogenesis by down-regulating the cyclin-dependent kinase inhibitor p57kip2. PloS one 20 20140255
2005 (1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: further optimisation as highly potent and selective MSK-1-inhibitors. Bioorganic & medicinal chemistry letters 20 15955699
2004 snf1lk encodes a protein kinase that may function in cell cycle regulation. Genomics 20 15177563
2021 Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1. Frontiers in molecular neuroscience 19 34295222
2016 Regulation of StAR by the N-terminal Domain and Coinduction of SIK1 and TIS11b/Znf36l1 in Single Cells. Frontiers in endocrinology 19 27531991
2023 Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation. Proceedings of the National Academy of Sciences of the United States of America 18 38147543
2022 MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy. Cells 18 35203255
2021 Exosomal microRNA-25 released from cancer cells targets SIK1 to promote hepatocellular carcinoma tumorigenesis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 18 34384713
2018 Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 29929190
2022 Circ_0078607 inhibits the progression of ovarian cancer via regulating the miR-32-5p/SIK1 network. Journal of ovarian research 17 34983607
2021 Role of SIK1 in the transition of acute kidney injury into chronic kidney disease. Journal of translational medicine 17 33588892
2017 Activation of the LKB1‑SIK1 signaling pathway inhibits the TGF‑β‑mediated epithelial‑mesenchymal transition and apoptosis resistance of ovarian carcinoma cells. Molecular medicine reports 17 29257268
2016 GINS complex protein Sld5 recruits SIK1 to activate MCM helicase during DNA replication. Cellular signalling 17 27592030
2025 SIK1 promotes ferroptosis resistance in pancreatic cancer via HDAC5-STAT6-SLC7A11 axis. Cancer letters 16 40250791
2021 QiShenYiQi ameliorates salt-induced hypertensive nephropathy by balancing ADRA1D and SIK1 expression in Dahl salt-sensitive rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 34328102
2020 lncRNA NR2F1-AS1 Regulates miR-17/SIK1 Axis to Suppress the Invasion and Migration of Cervical Squamous Cell Carcinoma Cells. Reproductive sciences (Thousand Oaks, Calif.) 16 31994002
2019 Adenovirus-mediated expression of SIK1 improves hepatic glucose and lipid metabolism in type 2 diabetes mellitus rats. PloS one 16 31233505
2018 Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. Human pathology 16 30121369
2013 Contribution of S6K1/MAPK signaling pathways in the response to oxidative stress: activation of RSK and MSK by hydrogen peroxide. PloS one 16 24058693
2010 The effects of 1,25-dihydroxyvitamin D3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling. The Journal of steroid biochemistry and molecular biology 16 20223287
2004 The phenylmethylthiazolylthiourea nonnucleoside reverse transcriptase (RT) inhibitor MSK-076 selects for a resistance mutation in the active site of human immunodeficiency virus type 2 RT. Journal of virology 16 15220416
2025 Polysaccharide from Pyrus pashia Buch ameliorates DSS-induced colitis in mice via MAPKP38/NF-κB P65 and SCFAs/ERK/MSK signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 15 40036991
2023 SIK1 suppresses colorectal cancer metastasis and chemoresistance via the TGF-β signaling pathway. Journal of Cancer 15 37670972
2020 Astroglia-Derived BDNF and MSK-1 Mediate Experience- and Diet-Dependent Synaptic Plasticity. Brain sciences 15 32708382
1991 Establishment of a sarcoma cell line, MS-K, expressing Ki-ras proto-oncogene product from mouse bone marrow stromal cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 2043753
2021 Oxycodone self-administration activates the mitogen-activated protein kinase/ mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum. Scientific reports 14 33510349
2020 Zhenqing recipe attenuates non-alcoholic fatty liver disease by regulating the SIK1/CRTC2 signaling in experimental diabetic rats. BMC complementary medicine and therapies 14 32020874
2020 Novel tumor mutation score versus tumor mutation burden in predicting survival after immunotherapy in pan-cancer patients from the MSK-IMPACT cohort. Annals of translational medicine 14 32395490
2020 SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. Frontiers in endocrinology 14 33013689
2024 Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis. Cell proliferation 13 38185757
2023 ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes. Journal of cellular physiology 12 36924049
2022 Design, synthesis and structural-activity relationship studies of phanginin A derivatives for regulating SIK1-cAMP/CREB signaling to suppress hepatic gluconeogenesis. European journal of medicinal chemistry 12 35152093
2021 Virulent Drexlervirial Bacteriophage MSK, Morphological and Genome Resemblance With Rtp Bacteriophage Inhibits the Multidrug-Resistant Bacteria. Frontiers in microbiology 12 34504479
2016 New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers. Urolithiasis 12 27573101
2023 The SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3β signaling pathways mediated by microRNA-25-3p are altered in the schizophrenic rat brain. Frontiers in cellular neuroscience 11 36744005
2021 Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake. Clinical and experimental hypertension (New York, N.Y. : 1993) 11 33688765
2019 Acute salt loading induces sympathetic nervous system overdrive in mice lacking salt-inducible kinase 1 (SIK1). Hypertension research : official journal of the Japanese Society of Hypertension 11 30894696
2013 Role of FGF10 on tumorigenesis by MS-K. Genes to cells : devoted to molecular & cellular mechanisms 11 24320134
2022 LKB1 inhibits proliferation, metastasis and angiogenesis of thyroid cancer by upregulating SIK1. Journal of Cancer 10 35912012
2018 Suppression of gluconeogenic gene transcription by SIK1-induced ubiquitination and degradation of CRTC1. Biochimica et biophysica acta. Gene regulatory mechanisms 10 29408765
2024 Demethylase FTO-mediated m6A modification of SIK1 modulates placental cytotrophoblast syncytialization in type 2 diabetes mellitus. iScience 9 38883837
2022 Novel mutation of SIK1 gene causing a mild form of pediatric epilepsy in a Chinese patient. Metabolic brain disease 8 35267137
2021 Iron distribution in different tissues of homozygous Mask (msk/msk) mice and the effects of oral iron treatments. American journal of hematology 8 34343368
2021 Implementation of a novel stratified PAthway of CarE for common musculoskeletal (MSK) conditions in primary care: protocol for a multicentre pragmatic randomised controlled trial (the PACE MSK trial). BMJ open 8 37039086
2024 miR-145a-5p/SIK1/cAMP-dependent alteration of synaptic structural plasticity drives cognitive impairment induced by coke oven emissions. Ecotoxicology and environmental safety 7 38677069
2021 Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. PloS one 7 34133426

Missed literature

Know a paper Affinage missed for SIK1? Flag it for the maintainers and the community.

No submissions yet.