Affinage

SIK1

Serine/threonine-protein kinase SIK1 · UniProt P57059

Length
783 aa
Mass
84.9 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIK1 is an LKB1-activated, AMPK-family serine/threonine kinase that functions as a central integrator of cAMP, energy, and stress signaling by phosphorylating transcriptional regulators to reshape gene expression programs in muscle, liver, brain, vasculature, and immune cells. Its principal substrates are CRTC coactivators (CRTC1–3), whose SIK1-mediated phosphorylation triggers 14-3-3 binding, nuclear export, and—in the case of CRTC1—RFWD2-dependent proteasomal degradation, thereby suppressing CREB-dependent transcription of gluconeogenic, circadian, and steroidogenic genes (PMID:23993098, PMID:29408765, PMID:25662274); SIK1 also phosphorylates class IIa HDACs (HDAC4/5) to drive their cytoplasmic translocation and activate MEF2-dependent myogenic and neuronal gene programs, and phosphorylates HDAC5-Ser498 to stabilize HDAC5 and promote STAT6-SLC7A11-mediated ferroptosis resistance (PMID:17468767, PMID:40250791). SIK1 activity is positively regulated by LKB1 phosphorylation at Thr182 and autophosphorylation at Ser186, and negatively regulated by AKT- and PKA-mediated phosphorylation that promotes 14-3-3 binding, cytoplasmic sequestration, and ITCH-dependent ubiquitin–proteasomal degradation (PMID:18946175, PMID:36806887). De novo mutations in SIK1 cause a developmental epileptic encephalopathy, with disease-associated truncations shifting SIK1 from nuclear to cytoplasmic distribution without abolishing kinase activity, disrupting excitatory/inhibitory synaptic balance (PMID:25839329, PMID:34295222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 Low

    Early characterization showed that forced expression of the SIK1 kinase domain causes endoreduplication without division, hinting at a cell-cycle regulatory role, but the molecular target was unknown.

    Evidence Inducible kinase-domain expression in CHO cells with flow cytometry and in situ hybridization in mouse embryos

    PMID:15177563

    Open questions at the time
    • No substrate or downstream pathway identified
    • Overexpression artifact not ruled out
    • Endoreduplication phenotype not independently confirmed
  2. 2007 High

    Two studies established SIK1's first direct substrates and physiological roles: SIK1 phosphorylates class IIa HDACs to activate MEF2-dependent muscle gene expression, and SIK1 phosphorylates PME-1 at the Na+,K+-ATPase complex to regulate sodium transport, revealing SIK1 as a signal-responsive kinase with both transcriptional and metabolic outputs.

    Evidence Viral re-expression in dystrophic mice with MEF2 reporter and HDAC phosphorylation assays; co-IP, in vitro kinase assay, and sodium-loading experiments in renal epithelial cells

    PMID:17468767 PMID:17939993

    Open questions at the time
    • Whether HDAC phosphorylation sites are identical to those used by other AMPK-family kinases was not resolved
    • The CaM kinase–Thr322 activation axis for SIK1 at the NK complex was not confirmed in vivo
  3. 2008 High

    The activation mechanism of SIK1 was dissected: LKB1 phosphorylates Thr182 to initiate activity, SIK1 auto-phosphorylates Ser186 for sustained signaling, and GSK-3β contributes to maintaining the Ser186 phosphosite, placing SIK1 at a convergence of LKB1 and Wnt/insulin pathways.

    Evidence In vitro kinase assay with purified kinases, mutagenesis, AICAR-treated C2C12 myoblasts with subcellular fractionation

    PMID:18946175

    Open questions at the time
    • Structural basis for LKB1→SIK1→auto-phosphorylation cascade not determined
    • Contribution of GSK-3β in vivo remains indirect
  4. 2009 High

    A kinome-wide screen revealed that SIK1 is essential for LKB1-dependent p53 activation during anoikis, establishing SIK1 as a tumor suppressor that prevents anchorage-independent growth and metastasis.

    Evidence RNAi screen, in vitro anoikis assays, soft agar, and mouse metastasis model with epistasis analysis

    PMID:19622832

    Open questions at the time
    • Direct SIK1 substrate linking to p53 stabilization not identified
    • Whether SIK1 tumor-suppressive function is kinase-activity-dependent was not tested
  5. 2010 Medium

    SIK1 knockout ES cells revealed a role in cardiomyocyte differentiation via p57Kip2-dependent cell-cycle exit, broadening SIK1's functions beyond skeletal muscle.

    Evidence Gene-trap null ES cells, embryoid body differentiation, expression profiling, cell-cycle analysis

    PMID:20140255

    Open questions at the time
    • Mechanism by which SIK1 controls p57Kip2 expression is unknown
    • Not validated in whole-animal cardiac development
  6. 2012 High

    PKA phosphorylation of SIK1 at Thr475 was shown to stabilize SIK1 protein by protecting it from proteasomal degradation, revealing a feed-forward mechanism wherein cAMP signaling sustains SIK1 levels during myogenic differentiation.

    Evidence Cycloheximide chase, cell-free PKA kinase assay, PEST-domain and Thr475 mutagenesis, primary myoblast siRNA knockdown

    PMID:23256157

    Open questions at the time
    • E3 ligase responsible for basal SIK1 turnover in myoblasts was not identified at this time
  7. 2013 High

    SIK1 was placed in the circadian clock as a light-induced negative-feedback kinase: SIK1 phosphorylates and inactivates CRTC1 in the SCN to limit CREB-driven Per1 transcription, gating the magnitude of photic phase shifts.

    Evidence Transcriptomics of light-treated SCN, in vivo lentiviral shRNA knockdown of Sik1, behavioral phase-shift assays, CRTC1 phosphorylation measurements

    PMID:23993098

    Open questions at the time
    • Whether SIK2/SIK3 have redundant roles in circadian entrainment was not fully dissected
    • CRTC1 phosphorylation sites targeted by SIK1 in SCN not mapped
  8. 2015 High

    Multiple 2015 studies expanded SIK1's substrate repertoire and disease connections: SIK1 phosphorylates SR-B1 Ser496 to stimulate HDL cholesterol uptake; SIK1 represses StAR via CRTC2 in steroidogenic cells; SIK1 loss in vascular smooth muscle derepresses TGF-β1/endothelin-1 to elevate blood pressure on high-salt diet; and de novo SIK1 mutations cause developmental epilepsy through altered subcellular localization rather than loss of kinase activity.

    Evidence In vitro kinase assays, co-IP, mutagenesis, HDL-CE uptake assay, single-cell FISH, SIK1 KO mice on high-salt diet, patient-derived cell immunofluorescence and cycloheximide chase

    PMID:25556206 PMID:25662274 PMID:25839329 PMID:26567857

    Open questions at the time
    • Whether SR-B1 phosphorylation occurs in vivo at the hepatic level is unknown
    • Epilepsy-causing mutations' effect on specific HDAC or CRTC substrates in neurons not fully resolved
  9. 2016 High

    SIK1 was shown to suppress Wnt/β-catenin signaling by phosphorylating SMRT-Thr1391, promoting NCoR/SMRT–TBL1 complex formation and displacing β-catenin, establishing a direct kinase-substrate mechanism for SIK1's tumor-suppressive role in hepatocellular carcinoma.

    Evidence In vitro kinase assay, co-IP, ChIP, SMRT-T1391A mutagenesis, xenograft tumor models

    PMID:26778753

    Open questions at the time
    • Whether SMRT phosphorylation by SIK1 operates in non-hepatic Wnt-driven cancers is untested
  10. 2016 Medium

    SIK1 was found to interact with the GINS complex subunit Sld5 and phosphorylate MCM2 at N-terminal residues required for helicase activation, linking SIK1 to DNA replication initiation.

    Evidence Co-IP, in vitro kinase assay of MCM2, siRNA knockdown, DNA replication assays, chromatin fractionation

    PMID:27592030

    Open questions at the time
    • Independent confirmation of SIK1–GINS interaction is lacking
    • Whether kinase-dead SIK1 phenocopies the replication defect is untested
    • In vivo relevance to replication licensing not established
  11. 2018 High

    The CRTC1 phosphorylation mechanism by SIK1 was mapped to four specific serine sites, and downstream K48-ubiquitination via RFWD2 was identified, explaining how SIK1 specifically targets CRTC1 for proteasomal degradation to suppress gluconeogenic gene expression.

    Evidence In vitro kinase assay, phosphosite mutagenesis, ubiquitination assay with proteasome inhibitor, PEPCK luciferase reporter

    PMID:29408765

    Open questions at the time
    • Whether RFWD2-mediated CRTC1 degradation is regulated by feeding/fasting in vivo is unknown
  12. 2019 High

    Genetic studies in Kras-driven lung cancer models demonstrated that SIK1 (with SIK3) is the critical tumor-suppressive effector downstream of LKB1, acting through CRTC2 to restrain AP1 and IL-6 pro-tumorigenic transcription.

    Evidence CRISPR deletion of Sik1 in NSCLC cell lines and conditional mouse models, gene expression analysis, epistasis with CRTC2

    PMID:31350328

    Open questions at the time
    • Individual contribution of SIK1 vs. SIK3 not fully separated
    • Whether pharmacological SIK activation could substitute for LKB1 loss in NSCLC is unexplored
  13. 2020 Medium

    Two studies revealed additional SIK1 regulatory outputs: SIK1 activates PDE4 to degrade cAMP independently of CRTC phosphorylation, providing an extra brake on hepatic gluconeogenesis; and PKA phosphorylation of SIK1 at Ser577 suppresses sleep need, as shown by increased NREM sleep in Sik1-S577A knock-in mice.

    Evidence Primary hepatocyte assays, PDE4 activity measurement, ob/ob mouse model; CRISPR Sik1-S577A knock-in mice with EEG/EMG sleep recording

    PMID:32457359 PMID:32599076

    Open questions at the time
    • Direct SIK1 phosphorylation site on PDE4 is not identified
    • Sleep phenotype mechanism (which SIK1 substrate in neurons) is unknown
  14. 2021 Medium

    CRISPR knock-in mice bearing autism/epilepsy-associated SIK1 truncations showed that cytoplasmic mislocalization of mutant SIK1 increases excitatory synaptic transmission and disrupts cortical E/I balance, providing a circuit-level mechanism for the neurodevelopmental phenotype.

    Evidence CRISPR/Cas9 knock-in mice, immunofluorescence, whole-cell electrophysiology, behavioral assays

    PMID:34295222

    Open questions at the time
    • Whether mislocalized SIK1 gains cytoplasmic substrates or loses nuclear ones is unresolved
    • Specific synaptic SIK1 substrates not identified
  15. 2023 High

    The full degradation cascade for SIK1 in cancer was delineated: AKT phosphorylates SIK1, enabling 14-3-3 binding and cytoplasmic translocation, where Pin1 isomerase facilitates ITCH-mediated ubiquitination and proteasomal destruction, thereby relieving SIK1 repression of STAT3 and promoting tumor progression.

    Evidence MS-based interactomics, co-IP, in vitro kinase assay, ubiquitination assay, mutagenesis, breast cancer cell phenotypic assays

    PMID:36806887

    Open questions at the time
    • Whether ITCH-mediated SIK1 degradation operates outside breast cancer contexts is untested
    • Relative contributions of AKT vs. PKA to SIK1 cytoplasmic translocation not compared
  16. 2023 High

    Structure-based SIK1/2-selective inhibitors validated the CRTC-CREB axis as the key anti-inflammatory output of SIK activity: inhibition dephosphorylates CRTC3 at Ser329, suppresses pro-inflammatory cytokines, and induces IL-10 in macrophages.

    Evidence Structure-based inhibitor design, in vitro kinase selectivity panel, phospho-CRTC3 cellular assay, LPS-stimulated macrophage assay, murine colitis model

    PMID:38147543

    Open questions at the time
    • Whether SIK1 or SIK2 is the dominant isoform controlling innate immune cytokine balance is not resolved
    • Long-term immunological consequences of SIK inhibition unknown
  17. 2025 High

    A new SIK1–HDAC5 axis was uncovered in pancreatic cancer: SIK1 phosphorylates HDAC5 at Ser498, stabilizing it via 14-3-3 and protecting it from TRIM28-mediated degradation; stabilized HDAC5 deacetylates STAT6 to drive SLC7A11 expression and ferroptosis resistance.

    Evidence In vitro kinase assay, co-IP, ubiquitination assay, mutagenesis, organoid and PDX models

    PMID:40250791

    Open questions at the time
    • Whether HDAC5-Ser498 phosphorylation is a general SIK1 output across tissues or context-specific is unknown
    • Relationship between ferroptosis-protective and tumor-suppressive functions of SIK1 is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SIK1's substrate selectivity versus SIK2/SIK3, the identity of neuronal substrates responsible for E/I imbalance in SIK1-associated epilepsy, and how context determines whether SIK1 acts as tumor suppressor (via CRTC/SMRT) or tumor promoter (via HDAC5-STAT6-ferroptosis resistance).
  • No crystal structure of full-length SIK1 available
  • Neuronal SIK1 substrates causing synaptic phenotype unidentified
  • Context-dependency of SIK1 pro- vs anti-tumor effects not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9909396 Circadian clock 2 R-HSA-168256 Immune System 1
Partners
14-3-3CRTC1CRTC2HDAC4HDAC5LKB1SMRTSR-B1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SIK1 functions as a class II HDAC kinase: it directly phosphorylates class II HDACs (e.g., HDAC5), causing their nuclear export and thereby activating MEF2 transcription factors in skeletal myocytes. SIK1 is transcriptionally induced by CREB in response to cAMP signals, establishing a CREB→SIK1→HDAC→MEF2 pathway essential for muscle gene expression and survival. Viral re-expression of SIK1 in M-ACREB transgenic mice, measurement of class II HDAC phosphorylation, MEF2 reporter assays, dystrophic phenotype rescue Nature medicine High 17468767
2008 SIK1 (Thr182) is activated by LKB1-mediated phosphorylation; activated SIK1 then auto-phosphorylates Ser186 (a +4 position site). The Ser186 phospho-site is required for sustained SIK1 activity and is maintained by sequential phosphorylation involving GSK-3β. In C2C12 myoblasts treated with the AMPK agonist AICAR, SIK1 phosphorylates and causes nuclear export of HDAC5, leading to MEF2C activation and PGC-1α gene expression. In vitro kinase assay with GSK-3β purified from AICAR-treated cells, overexpression of SIK1, inhibitor studies, subcellular fractionation Endocrine journal High 18946175
2007 SIK1 constitutively associates with the Na+,K+-ATPase (NK) regulatory complex and regulates active sodium transport. Elevated intracellular Na+ triggers Ca2+ influx via the Na+/Ca2+ exchanger, which activates SIK1 via CaM kinase-mediated phosphorylation at Thr-322. Activated SIK1 then phosphorylates PME-1 (phosphatase methylesterase-1), causing its dissociation from a PP2A/PME-1 complex on the NK α-subunit, leading to NK α-subunit dephosphorylation and increased catalytic activity. Co-immunoprecipitation, in vitro phosphorylation assays, calcium imaging, sodium loading experiments, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 17939993
2009 SIK1 mediates LKB1-dependent p53 activation during anoikis: SIK1 is required downstream of LKB1 for p53-dependent apoptosis triggered by cell detachment. Loss of SIK1 compromises p53 function and permits anchorage-independent growth and metastatic spread in vivo. Kinome-wide loss-of-function RNAi screen, in vitro anoikis assays, anchorage-independent growth, in vivo mouse metastasis model, epistasis analysis Science signaling High 19622832
2013 In the circadian clock, light-induced CRTC1 coactivates CREB to drive Per1 and Sik1 transcription. SIK1 then creates a negative feedback loop by phosphorylating and inactivating CRTC1, suppressing further light-induced clock shifts. Knockdown of Sik1 in the SCN increases phase shifts and accelerates re-entrainment after jet lag. Transcriptome analysis of light-regulated SCN genes, in vivo Sik1 knockdown via SCN-targeted lentiviral shRNA, behavioral phase-shift assays, CRTC1 phosphorylation measurements Cell High 23993098
2019 SIK1 and SIK3 mediate key tumor-suppressive effects of LKB1 in NSCLC: conditional genetic loss of Sik1 increases tumor growth in Kras-driven lung cancer mouse models. SIK1/3 loss upregulates AP1 and IL-6 signaling via the SIK substrate CRTC2, which is required for proliferation benefits from SIK loss, placing SIK1 downstream of LKB1 in suppressing CRTC2-driven transcription. CRISPR-based genetic deletion in NSCLC cell lines and conditional mouse models, gene expression analysis, epistasis with CRTC2 Cancer discovery High 31350328
2012 SIK1 protein stability during myogenesis is regulated by PKA-mediated phosphorylation at Thr475 within a PEST domain: PKA phosphorylation of Thr475 extends SIK1 half-life by protecting it from proteasomal degradation. In cell-free assays PKA directly phosphorylates Thr475. SIK1 depletion in primary muscle precursor cells impairs MEF2 protein accumulation and myogenic differentiation. Cycloheximide chase assays, cell-free PKA phosphorylation assay, mutagenesis of Thr475 and PEST domain, primary myoblast siRNA knockdown, differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 23256157
2016 SIK1 phosphorylates SMRT at Thr1391, which promotes NCoR/SMRT association with TBL1/TBLR1 and disrupts β-catenin binding to the TBL1/TBLR1 complex, thereby inactivating Wnt/β-catenin transcriptional activity. SMRT-T1391A mutant reverses the tumor-suppressive effect of SIK1. In vitro kinase assay, immunoprecipitation, luciferase reporter, ChIP, SMRT phosphorylation-site mutagenesis, xenograft tumor models Journal of hepatology High 26778753
2015 SIK1 mutations causing developmental epilepsy occur outside the kinase domain; mutant SIK1 proteins retain autophosphorylation and kinase activity toward HDAC5 but show altered subcellular localization (nuclear vs. cytoplasmic distribution) compared to wild-type SIK1. Truncated mutants are resistant to proteasomal degradation. In vitro autophosphorylation and HDAC5 kinase assays, subcellular fractionation and immunofluorescence in patient-derived cells and transfected cells, cycloheximide chase American journal of human genetics High 25839329
2015 SIK1 forms a complex with SR-B1 via its cytoplasmic C-terminal domain and directly phosphorylates the SR-B1 C-terminal domain. In vitro kinase assays show SIK1-catalyzed phosphorylation of SR-B1 Ser496 is critical for stimulation of selective HDL cholesteryl ester uptake and steroidogenesis. Both SIK1 catalytic activity and its PKA-mediated phosphorylation are required for SR-B1 activation. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of SR-B1 Ser496, HDL-BODIPY-CE uptake assay, SIK1 overexpression and knockdown Biochemistry High 26567857
2016 SIK1 is recruited to sites of DNA replication via direct interaction with Sld5, a component of the GINS complex. SIK1 phosphorylates MCM2 at five conserved N-terminal residues, which is required for MCM helicase activation. SIK1 depletion causes defective DNA replication. Co-immunoprecipitation, in vitro kinase assay of MCM2 phosphorylation, siRNA knockdown, DNA replication assays, chromatin fractionation Cellular signalling Medium 27592030
2017 RNF2 functions as an E3 ubiquitin ligase that directly binds SIK1 and targets it for ubiquitin-mediated proteasomal degradation in hepatocellular carcinoma cells, providing a mechanism for SIK1 downregulation. Co-immunoprecipitation, ubiquitination assay, RNF2 knockdown and overexpression, xenograft models Oncotarget Medium 27911266
2018 SIK1 suppresses gluconeogenic gene transcription by phosphorylating CRTC1 at S155, S167, S188, and S346, triggering K48-linked polyubiquitination via the RFWD2 ubiquitin ligase and proteasomal degradation of CRTC1. This mechanism is specific to SIK1 (not SIK2 or SIK3). In vitro kinase assay, phosphorylation-site mutagenesis, ubiquitination assay, proteasome inhibitor experiments, PEPCK luciferase reporter, SIK1 knockdown and overexpression Biochimica et biophysica acta. Gene regulatory mechanisms High 29408765
2023 AKT directly binds SIK1 and phosphorylates it, relieving SIK1-mediated repression of STAT3 in a phosphorylation-dependent manner. AKT-phosphorylated SIK1 interacts with 14-3-3 and is translocated to the cytoplasm, where Pin1 isomerase facilitates SIK1 interaction with the E3 ligase ITCH, promoting SIK1 ubiquitination and degradation. Mass spectrometry-based interactomics, co-immunoprecipitation, in vitro kinase assay, subcellular fractionation, ubiquitination assay, mutagenesis, breast cancer cell phenotypic assays Cancer research High 36806887
2020 SIK1 activates phosphodiesterase 4 (PDE4), increasing cAMP degradation and thereby suppressing the cAMP/PKA/CREB pathway to inhibit hepatic gluconeogenesis. This mechanism is distinct from direct CRTC2 phosphorylation and represents an additional route by which SIK1 dampens cAMP signaling. Primary hepatocyte gluconeogenesis assay, siRNA knockdown of SIK1, pan-SIK inhibitor HG-9-91-01, SIK1 overexpression, direct PDE4 activity measurement, ob/ob mouse model Molecular metabolism Medium 32599076
2010 Sik1 knockout in mouse embryonic stem cells impairs cardiomyogenesis by reducing expression of the cyclin-dependent kinase inhibitor p57Kip2, delaying cell cycle exit required for terminal cardiomyocyte differentiation. Gene-trap sik1 null ES cells, embryoid body differentiation assay, expression profiling, cell cycle analysis PloS one Medium 20140255
2011 Cocaine activates SIK1 in rat striatum via phosphorylation at Thr-182, causing SIK1 nuclear import. Nuclear SIK1 then phosphorylates HDAC5, driving its nuclear-to-cytoplasmic shuttling and activating MEF2C transcription. SIK1 activation also causes nuclear export of TORC1/3 coactivators. In vivo cocaine treatment, phospho-Thr182 SIK1 immunoblot, subcellular fractionation for SIK1, HDAC5, and TORC1/3, MEF2C gene expression Synapse (New York, N.Y.) Medium 21954104
2015 In steroidogenic cells, SIK1 represses StAR expression through inhibition of CRTC2-mediated transcription and splicing processing. SIK1 is rapidly induced by cAMP/PKA signaling and provides a negative feedback brake on StAR gene activation. Fluorescence in situ hybridization (FISH) for StAR RNA in single cells, SIK1 overexpression and siRNA knockdown in Y1 and MA10 cells, qPCR Molecular and cellular endocrinology Medium 25662274
2020 PKA-mediated phosphorylation of SIK1 at its conserved site S577 negatively regulates sleep need: SIK1-S577A knock-in mice show increased NREM sleep time and higher NREM delta power, indicating that PKA phosphorylation of SIK1 suppresses sleep pressure. CRISPR knock-in mice (Sik1S577A), EEG/EMG sleep recording, sleep deprivation protocol, circadian behavior assays Scientific reports Medium 32457359
2021 SIK1 C-terminal truncation mutations associated with autism/epilepsy shift SIK1 subcellular distribution from exclusively nuclear to both nuclear and cytoplasmic. In SIK1-MT mice generated by CRISPR, this mislocalization is associated with increased excitatory synaptic transmission, disrupted E/I balance in cortical pyramidal neurons, and repetitive behavior. CRISPR/Cas9 knock-in mice, immunofluorescence localization, whole-cell electrophysiology, behavioral assays Frontiers in molecular neuroscience Medium 34295222
2025 SIK1 promotes ferroptosis resistance in pancreatic cancer via a HDAC5-STAT6-SLC7A11 axis: SIK1 phosphorylates HDAC5 at Ser498, promoting its interaction with 14-3-3 and protecting HDAC5 from TRIM28-mediated ubiquitination and degradation. Stabilized HDAC5 deacetylates STAT6, enhancing its transcriptional activation of SLC7A11, which confers resistance to ferroptosis. In vitro kinase assay (SIK1 phosphorylation of HDAC5 Ser498), co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, HDAC activity assay, organoid and PDX models Cancer letters High 40250791
2015 Arterial blood pressure regulation by SIK1 involves TGF-β1 signaling: SIK1 knockout mice on high-salt diet exhibit upregulated TGF-β1 signaling, increased endothelin-1 expression, and enhanced vascular smooth muscle cell contractile marker expression. In vitro SIK1 knockdown in VSMCs increases contractile markers and endothelin-1, while knockdown in adventitial fibroblasts increases collagen deposition. SIK1 knockout mouse model, high-salt diet challenge, in vitro SIK1 siRNA knockdown in VSMCs and fibroblasts, blood pressure telemetry, Western blot, histology Circulation research Medium 25556206
2023 SIK1-selective inhibitors that engage two differentiating features of the SIK catalytic site reduce phosphorylation of the SIK substrate CRTC3 at Ser329, suppress pro-inflammatory cytokine production, and induce anti-inflammatory IL-10 in myeloid cells following LPS challenge, demonstrating SIK1/2 as key regulators of innate immune cytokine balance via the CRTC-CREB axis. Structure-based inhibitor design, in vitro kinase selectivity panel, phospho-CRTC3 antibody-based cellular assay, LPS-stimulated macrophage cytokine assays, murine colitis model Proceedings of the National Academy of Sciences of the United States of America High 38147543
2014 Gastrin induces SIK1 expression in gastric adenocarcinoma cells via CCK2 receptor-Gq/G11 signaling, causing LKB1 Ser428 phosphorylation and SIK1 Thr182 phosphorylation. Activated SIK1 phosphorylates HDAC4 and promotes its nuclear export, enhancing CRE-, SRE-, AP1-, and NF-κB-driven transcription. SIK1 knockdown increases cell migration. SIK1 overexpression and siRNA knockdown, phosphorylation-specific immunoblot, luciferase reporter assays, subcellular fractionation of HDACs, transwell migration assay PloS one Medium 25384047
2004 SNF1LK (SIK1) kinase domain expression in CHO cells causes cell cycle arrest with re-replication to 8N and 16N DNA content without cell division, suggesting a role in G2/M regulation. The protein is expressed in early cardiac and skeletal muscle progenitor cells during mouse embryogenesis. Tetracycline-inducible SNF1LK kinase domain expression in CHO cells, flow cytometry DNA content analysis, in situ hybridization for developmental expression 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 1823 25801821
2007 SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature medicine 232 17468767
2006 Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Molecular cell 187 17081988
2021 Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01. Cell stem cell 185 33545080
2013 The CRTC1-SIK1 pathway regulates entrainment of the circadian clock. Cell 174 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 136 34308366
2009 SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Science signaling 134 19622832
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 131 28526081
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
2008 MSK activation and physiological roles. Frontiers in bioscience : a journal and virtual library 129 18508628
2021 Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS. Nature communications 127 34145282
2019 The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC. Cancer discovery 119 31350328
2018 The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants. Cell host & microbe 119 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 69 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 61 35780119
1992 Characterization of murine hemopoietic-supportive (MS-1 and MS-5) and non-supportive (MS-K) cell lines. Leukemia 61 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 54 21970321
2015 De novo mutations in SIK1 cause a spectrum of developmental epilepsies. American journal of human genetics 48 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 44 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
2015 The Hippo/STE20 homolog SIK1 interacts with MOB1 to regulate cell proliferation and cell expansion in Arabidopsis. Journal of experimental botany 39 26685188
2010 Intracellular sodium sensing: SIK1 network, hormone action and high blood pressure. Biochimica et biophysica acta 39 20347966
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
2012 Regulation of SIK1 abundance and stability is critical for myogenesis. Proceedings of the National Academy of Sciences of the United States of America 36 23256157
2019 MicroRNA-17 promotes cell proliferation and migration in human colorectal cancer by downregulating SIK1. Cancer management and research 35 31118777
2013 CALHM1 controls the Ca²⁺-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. Journal of cell science 35 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.) 35 21954104
2022 BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1. Cancer cell international 34 35346195
2017 Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis. Oncotarget 32 27911266
2023 AKT Blocks SIK1-Mediated Repression of STAT3 to Promote Breast Tumorigenesis. Cancer research 31 36806887
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
2020 Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need. Scientific reports 30 32457359
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 29 33545220
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
2020 Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway. Molecular metabolism 28 32599076
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
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
2020 Gut microbiota modulation by both Lactobacillus fermentum MSK 408 and ketogenic diet in a murine model of pentylenetetrazole-induced acute seizure. Epilepsy research 25 33276243
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
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
2004 snf1lk encodes a protein kinase that may function in cell cycle regulation. Genomics 19 15177563
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
2022 MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy. Cells 17 35203255
2021 Role of SIK1 in the transition of acute kidney injury into chronic kidney disease. Journal of translational medicine 17 33588892
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 17 29929190
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
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 16 38147543
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
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
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
2022 Circ_0078607 inhibits the progression of ovarian cancer via regulating the miR-32-5p/SIK1 network. Journal of ovarian research 15 34983607
2020 Astroglia-Derived BDNF and MSK-1 Mediate Experience- and Diet-Dependent Synaptic Plasticity. Brain sciences 15 32708382
2018 Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. Human pathology 15 30121369
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 15 20223287
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
2025 SIK1 promotes ferroptosis resistance in pancreatic cancer via HDAC5-STAT6-SLC7A11 axis. Cancer letters 14 40250791
2023 SIK1 suppresses colorectal cancer metastasis and chemoresistance via the TGF-β signaling pathway. Journal of Cancer 14 37670972
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
2024 Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis. Cell proliferation 13 38185757
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 13 33510349
2020 SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. Frontiers in endocrinology 13 33013689
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 12 40036991
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
2020 Zhenqing recipe attenuates non-alcoholic fatty liver disease by regulating the SIK1/CRTC2 signaling in experimental diabetic rats. BMC complementary medicine and therapies 12 32020874
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
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 10 36924049
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 9 29408765
2024 Demethylase FTO-mediated m6A modification of SIK1 modulates placental cytotrophoblast syncytialization in type 2 diabetes mellitus. iScience 8 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
2021 Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. PloS one 7 34133426