Affinage

SIK3

Serine/threonine-protein kinase SIK3 · UniProt Q9Y2K2

Length
1321 aa
Mass
144.9 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIK3 is an LKB1- and MST3-activated serine/threonine kinase that functions as a central signaling hub linking upstream cAMP/PKA and energy-sensing inputs to chromatin regulation, sleep homeostasis, skeletal development, metabolism, and immune polarization. Its core mechanism involves phosphorylation of class IIa HDACs (particularly HDAC4), promoting 14-3-3 binding and cytoplasmic sequestration of HDACs, which de-represses MEF2-dependent transcription programs controlling chondrocyte hypertrophy, glial ion/water homeostasis, circadian timing, and synaptic plasticity gene expression (PMID:23393134, PMID:22318228, PMID:31645458, PMID:36877841, PMID:38057370). PKA phosphorylation of SIK3 at S551 recruits 14-3-3 to SIK3 itself and is required for normal NREM sleep amounts and sleep need; both loss- and gain-of-function mutations at this site cause hypersomnia, establishing the PKA–SIK3–HDAC4 axis as the principal intracellular pathway controlling mammalian sleep duration (PMID:30254177, PMID:33558433, PMID:40324078). Beyond the HDAC4 branch, SIK3 regulates CRTC2/CRTC3 nuclear export to control RANKL expression in osteoblasts and mediates LKB1 tumor-suppressive signaling through CRTC2–AP1/IL6 in NSCLC, and promotes mTOR activity by driving DEPTOR degradation in chondrocytes (PMID:30377251, PMID:31350328, PMID:30232230).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 High

    Establishing that 14-3-3 proteins directly bind the LKB1-phosphorylated T-loop of SIK3 resolved how upstream activation is coupled to SIK3 catalytic competence and cytoplasmic retention.

    Evidence Tandem affinity purification, co-IP, T-loop mutant binding assays, and subcellular localization imaging in mammalian cells

    PMID:16306228

    Open questions at the time
    • Structural basis of 14-3-3–SIK3 interaction not determined
    • Whether T-loop phosphorylation is sufficient for full activation in vivo was not tested
  2. 2012 High

    Demonstrating that SIK3 phosphorylates HDAC4 to sequester it in the cytoplasm and release MEF2C-dependent transcription in chondrocytes established the core SIK3–HDAC4–MEF2 signaling axis and its first physiological role in skeletal development.

    Evidence SIK3 knockout mice with chondrocyte hypertrophy defects, HDAC4 localization rescue, and epistasis analysis

    PMID:22318228 PMID:23393134

    Open questions at the time
    • Direct phosphorylation sites on HDAC4 mapped only generically to conserved motifs
    • Relative contributions of SIK3 versus SIK2 to HDAC phosphorylation in vivo not fully separated
  3. 2012 Medium

    SIK3 knockout mouse metabolic phenotyping revealed roles in glucose and lipid homeostasis beyond the skeleton, broadening SIK3's physiological scope to include adipose and hepatic metabolism.

    Evidence SIK3 knockout mice showing lipodystrophy, hypoglycemia, cholestasis; pharmacological rescue with 9-cis-retinoic acid

    PMID:22662228

    Open questions at the time
    • Direct substrates mediating metabolic effects not identified
    • Pathway placement inferred rather than biochemically reconstituted
  4. 2015 High

    Drosophila genetic epistasis placed SIK3 downstream of fasting/glucagon-like signals and insulin, and upstream of HDAC4 nuclear entry and lipolytic gene expression, providing a complete hormonal pathway from organismal energy state to lipid catabolism.

    Evidence Drosophila fat body genetics, SIK3 phosphorylation assays, HDAC4 localization, mutant rescue

    PMID:25996931

    Open questions at the time
    • Whether insulin and glucagon pathways converge on the same SIK3 phosphosite not resolved
    • Mammalian conservation of this specific lipolytic circuit not tested
  5. 2016 High

    Pharmacological inhibition (pterosin B) and conditional knockout of SIK3 in chondrocytes prevented osteoarthritis, establishing SIK3 as a druggable target in cartilage disease, while catalytically inactive SIK knock-in mice revealed that SIK3 kinase activity is required for pro-inflammatory macrophage polarization.

    Evidence Chondrocyte-specific SIK3 cKO mice plus intraarticular pterosin B; catalytically inactive SIK2/SIK3 knock-in mice with macrophage cytokine profiling

    PMID:27009967 PMID:27920213

    Open questions at the time
    • Molecular targets of SIK3 in macrophages not identified
    • Selectivity of pterosin B across SIK family not fully characterized
  6. 2017 Medium

    Showing that SIK3 in Drosophila clock neurons regulates HDAC4 shuttling and non-cell-autonomously controls PERIOD cycling in downstream neurons first linked SIK3-HDAC4 to circadian timing.

    Evidence Tissue-specific Sik3 knockdown in Drosophila morning clock neurons, circadian behavioral assays, HDAC4 localization

    PMID:28743754

    Open questions at the time
    • Mechanism of non-cell-autonomous signal transmission from M cells to DN1 neurons unknown
    • Mammalian circadian role not yet demonstrated at this time point
  7. 2018 High

    Identification of PKA phosphorylation at S551 as the site mediating 14-3-3 binding to SIK3 itself, and demonstration that point mutations at this site reproduce the Sleepy hypersomnia phenotype, established the PKA–SIK3 axis as the molecular switch controlling mammalian NREM sleep need.

    Evidence S551A and S551D knock-in mice with EEG/EMG, 14-3-3 binding assays, PKA recognition assays

    PMID:30254177

    Open questions at the time
    • How S551 phosphorylation status is regulated by wakefulness-associated neuromodulators not determined
    • Direct downstream phospho-targets of SIK3 in sleep-regulating neurons not identified
  8. 2018 High

    Linking a human SIK3 loss-of-function mutation to DEPTOR accumulation and reduced mTOR activity in chondrocytes revealed a second effector arm (mTOR via DEPTOR) distinct from the HDAC4 pathway, explaining additional aspects of skeletal disease.

    Evidence Patient-derived chondrocytes with SIK3 mutation, JMC disease model, DEPTOR/mTOR western blotting

    PMID:30232230

    Open questions at the time
    • Whether SIK3 directly phosphorylates DEPTOR or acts indirectly not resolved
    • Generalizability of DEPTOR mechanism beyond chondrocytes unknown
  9. 2018 Medium

    Placing SIK3 downstream of PTH/PKA and upstream of CRTC2/CRTC3 nuclear export in osteoblasts expanded the substrate repertoire to include CRTCs and linked the kinase to RANKL-driven bone remodeling.

    Evidence siRNA knockdown of SIK2/SIK3/CRTC3 in primary osteoblasts, CRTC localization imaging, cAMP/PKA assays

    PMID:30377251

    Open questions at the time
    • Relative contribution of SIK3 versus SIK2 to CRTC phosphorylation not dissected
    • In vivo bone phenotype of SIK3-only loss not shown in this study
  10. 2019 High

    Genetic studies in NSCLC models showed SIK1/SIK3 double loss recapitulates LKB1 tumor-suppressive loss via CRTC2–AP1/IL6, positioning SIK3 as a key LKB1 effector in cancer suppression.

    Evidence CRISPR knockout in NSCLC lines, Kras-driven mouse lung cancer models, CRTC2 requirement testing

    PMID:31350328

    Open questions at the time
    • Whether SIK3 alone is sufficient for tumor suppression without SIK1 not clear
    • Patient-derived genomic evidence for SIK3 loss in NSCLC not presented
  11. 2019 High

    Demonstrating that SIK3 in Drosophila glia drives MEF2-dependent expression of K+ and water transport genes via HDAC4 cytoplasmic retention established a glial-autonomous role for SIK3 in ion homeostasis and seizure prevention.

    Evidence Glial-specific SIK3 loss-of-function in Drosophila, HDAC4 localization, electrophysiology, transcriptional analysis

    PMID:31645458

    Open questions at the time
    • Mammalian glial conservation not demonstrated
    • Whether SIK3 regulation of K+ homeostasis contributes to its sleep phenotype not tested
  12. 2021 Medium

    Neuron-specific inducible expression of the gain-of-function SIK3(SLP) allele proved that neuronal SIK3 activity is sufficient for the hypersomnia phenotype, excluding peripheral contributions.

    Evidence Inducible Cre-mediated SIK3(SLP) expression in mature neurons, EEG/EMG sleep analysis

    PMID:33558433

    Open questions at the time
    • Which neuronal populations are responsible not resolved
    • Whether the SLP truncation creates a neomorphic function not excluded
  13. 2022 High

    Identification of MST3 as an alternative upstream kinase that directly phosphorylates and activates SIK3 independently of LKB1 expanded the activation logic of SIK3 beyond the canonical AMPK-related kinase pathway.

    Evidence In vitro kinase reconstitution with purified MST3 and SIK3, in vivo phosphorylation in HEK cells

    PMID:35413286

    Open questions at the time
    • Physiological context in which MST3 rather than LKB1 activates SIK3 not determined
    • Whether MST3 and LKB1 phosphorylate identical or overlapping T-loop sites not mapped
  14. 2023 High

    Demonstrating that SIK3 deficiency in SCN GABAergic/NMS neurons delays arousal and lengthens circadian period, while HDAC4 S245A knock-in phenocopies the delay, established the SIK3–HDAC4 axis as a circadian period regulator in the master clock.

    Evidence Cell-type-specific SIK3 cKO and gain-of-function mice, HDAC4 S245A knock-in, EEG/EMG and circadian behavioral assays

    PMID:36877841

    Open questions at the time
    • Transcriptional targets downstream of HDAC4 in SCN neurons not identified
    • How SIK3-HDAC4 integrates with core clock gene oscillations unknown
  15. 2023 Medium

    Co-IP and ChIP-qPCR in hippocampal neurons placed SIK3–HDAC4–MEF2C at synaptic plasticity gene promoters, and conditional SIK3 deletion accelerated cognitive decline in an Alzheimer's model, extending the axis to neurodegeneration.

    Evidence Co-IP, ChIP-qPCR, immunofluorescence, conditional hippocampal SIK3 deletion, electrophysiology in AD model mice

    PMID:38057370

    Open questions at the time
    • Causal relationship between SIK3 loss and amyloid/tau pathology not established
    • Single lab finding awaits independent replication
  16. 2025 High

    The human Natural Short Sleep SIK3-N783Y mutation was shown to reduce kinase activity and decrease sleep time while altering synaptic phosphoproteomes enriched for PKA/MAPK substrates, providing the first human genetic variant linking SIK3 to sleep duration and revealing its broad signaling footprint at synapses.

    Evidence In vitro kinase assay, knock-in mouse EEG/EMG, phosphoproteomics

    PMID:40324078

    Open questions at the time
    • How N783Y allele affects HDAC4 phosphorylation specifically not tested
    • Whether PKA/MAPK phosphoproteomic changes are direct or indirect SIK3 effects unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct phospho-substrates of SIK3 in sleep-regulating neurons, the structural basis for SIK3 regulation by S551 phosphorylation and 14-3-3 binding, and whether the HDAC4 and CRTC effector arms operate in parallel or are cell-type-segregated remain major open questions.
  • No crystal structure or cryo-EM model of SIK3 available
  • Neuron-type-specific substrates of SIK3 not catalogued
  • Integration of HDAC4 and CRTC branches across tissues not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-9909396 Circadian clock 2 R-HSA-168256 Immune System 1
Partners
CRTC2CRTC3DEPTORHDAC4LKB1MEF2CMST3YWHAZ

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 14-3-3 isoforms bind directly to the phosphorylated T-loop threonine of SIK3 (after LKB1-mediated phosphorylation), enhancing catalytic activity and requiring 14-3-3 binding for cytoplasmic localization of SIK3; mutation of the T-loop Thr prevents 14-3-3 interaction in vitro. Tandem affinity purification, co-immunoprecipitation, in vitro binding assays with T-loop mutants, subcellular localization imaging Journal of cell science High 16306228
2013 LKB1 acts through SIK3 (and SIK2) to phosphorylate class IIa HDACs (HDAC4, -5, -7, -9) at conserved motifs, stimulating 14-3-3 binding and nuclear export; SIK3 can induce nuclear export of HDACs independent of kinase activity and 14-3-3 binding, distinguishing it mechanistically from SIK2. Kinase assays, co-immunoprecipitation, subcellular localization by fluorescence microscopy, dominant-negative and kinase-dead mutant analysis The Journal of biological chemistry High 23393134
2012 SIK3 is required for chondrocyte hypertrophy during skeletal development: SIK3 phosphorylates and anchors HDAC4 in the cytoplasm, thereby releasing MEF2C from nuclear HDAC4-mediated repression to facilitate hypertrophic gene expression. SIK3 knockout mice, chondrocyte-specific overexpression/rescue, HDAC4 subcellular localization by immunofluorescence, histology Development (Cambridge, England) High 22318228
2012 SIK3 regulates glucose and lipid homeostasis in mice; SIK3-deficient mice display lipodystrophy, hypoglycemia, and hyper-insulin sensitivity associated with reduced fatty acid synthesis gene expression, and cholestasis linked to dysregulated retinoid/nuclear receptor signaling. SIK3 knockout mouse phenotyping, gene expression analysis, pharmacological rescue with 9-cis-retinoic acid PloS one Medium 22662228
2015 In Drosophila, the LKB1-SIK3-HDAC4 axis controls lipid metabolism: fasting signals (via adipokinetic hormone/glucagon-like pathway) reduce LKB1-mediated SIK3 T196 phosphorylation, decreasing SIK3 activity, which allows HDAC4 nuclear localization and brummer (ATGL homolog) gene expression to promote lipolysis; insulin independently regulates SIK3 activity in feeding conditions. Genetic epistasis in Drosophila fat body, biochemical SIK3 phosphorylation assays, HDAC4 nuclear localization imaging, mutant rescue PLoS genetics High 25996931
2016 Pterosin B inhibits the SIK3 pathway and prevents chondrocyte hypertrophy; chondrocyte-specific SIK3 conditional knockout mice are resistant to osteoarthritis with thickened articular cartilage and a larger chondrocyte population. Conditional knockout mice, intraarticular drug injection, histology, kinase inhibition assay Nature communications High 27009967
2016 SIK2 and SIK3 (and SIK1) are required for macrophage polarization; knock-in mice with catalytically inactive SIK2/SIK3 reveal that inhibition of these isoforms during macrophage differentiation drives a stable anti-inflammatory phenotype with high IL-10 and low TNFα even after kinase reactivation. Catalytically inactive knock-in mice for each SIK isoform, primary macrophage cytokine profiling, pharmacological SIK inhibitors The Biochemical journal High 27920213
2018 A single PKA phosphorylation site on SIK3 (S551) mediates 14-3-3 binding and regulates daily NREMS amounts and sleep need: S551A and S551D mutations each reproduce the hypersomnia phenotype of Sleepy mutant mice, and deletion or mutation at S551 reduces PKA recognition and abolishes 14-3-3 binding. Point-mutant knock-in mice (S551A, S551D), EEG/EMG sleep analysis, 14-3-3 binding assays, PKA recognition assay Proceedings of the National Academy of Sciences of the United States of America High 30254177
2018 PTH/PTHrP signaling acts through SIK3 to regulate mTOR activity in chondrocytes; a loss-of-function SIK3 mutation causes accumulation of DEPTOR (a negative regulator of mTOR), reducing mTORC1 and mTORC2 activity, establishing SIK3 as a positive regulator of mTOR via DEPTOR degradation during skeletogenesis. Patient-derived chondrocytes with SIK3 mutation, JMC disease model, mTOR/DEPTOR western blotting, PTHrP receptor activation assays Science translational medicine High 30232230
2018 In osteoblasts, PTH(1-34) inhibits SIK2 and SIK3 via PKA, leading to nuclear localization of CRTC2/CRTC3 and regulation of Rankl expression; SIK2/SIK3 knockdown and PP1/PP2A inhibition place these kinases and phosphatases in the pathway controlling CRTC3 nuclear export and Rankl transcription. siRNA knockdown of SIK2, SIK3, CRTC3 in primary calvarial osteoblasts, CRTC localization imaging, cAMP/PKA assays, in vivo Rankl measurement The Journal of biological chemistry Medium 30377251
2019 SIK1 and SIK3 mediate key tumor-suppressive effects of LKB1 in NSCLC; genetic loss of Sik3 (combined with Sik1) increases tumor growth in Kras-driven lung cancer mouse models; the SIK substrate CRTC2 is required for AP1/IL6 upregulation and proliferation benefits seen upon SIK1/3 loss. CRISPR knockout in NSCLC cell lines, conditional mouse models, gene expression analysis, CRTC2 genetic requirement test Cancer discovery High 31350328
2017 In Drosophila, SIK3 in morning clock neurons (M cells) regulates male sex drive rhythm non-cell-autonomously by modulating HDAC4 nucleocytoplasmic shuttling; loss of Sik3 in M cells disrupts PERIOD cycling in DN1 neurons and constitutive nuclear HDAC4 shortens the MSDR period. Tissue-specific Sik3 knockdown in Drosophila, circadian behavioral assays, HDAC4 localization imaging in clock neurons Proceedings of the National Academy of Sciences of the United States of America Medium 28743754
2019 SIK3 in Drosophila glia controls extracellular K+ and water homeostasis by promoting cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K+ and water transport molecules; loss of SIK3 causes fluid accumulation in nerves, neuronal hyperexcitability, and seizures. Drosophila glial-specific SIK3 loss-of-function, HDAC4 localization, electrophysiology, seizure behavioral assay, transcriptional analysis The Journal of cell biology High 31645458
2022 MST3 (mammalian sterile 20-like kinase 3) is a new upstream kinase that can phosphorylate and activate SIK3 independently of LKB1; recombinant MST3 directly phosphorylates SIK3 in vitro, and MST3 from human embryonic kidney cells phosphorylates SIK3 in vivo. Biochemical purification of phosphorylation activity, in vitro kinase assay with purified recombinant MST3 and SIK3, in vivo phosphorylation in HEK cells The Journal of biological chemistry High 35413286
2019 SIK3 promotes chondrocyte maturation by increasing acetyl-CoA levels through suppression of PDK4 (pyruvate dehydrogenase kinase 4), thereby maintaining active PDH and pyruvate-to-acetyl-CoA flux; SIK3 knockout chondrocytes show elevated phospho-PDH and PDK4 with decreased acetyl-CoA. Metabolome analysis of Sik3 KO chondrocytes, immunohistochemistry for phospho-PDH and PDK4, organ culture with PDH inhibitor Biochemical and biophysical research communications Medium 31280862
2021 Neuron-specific expression of the gain-of-function SIK3(SLP) mutant allele in mature neurons (after late infancy) is sufficient to increase NREMS amounts and NREMS delta power, establishing that SIK3 signaling in neurons (not peripheral tissues) underlies sleep homeostasis. Inducible Cre-mediated conditional expression of SIK3(SLP) in neurons, EEG/EMG sleep analysis The Journal of neuroscience Medium 33558433
2023 SIK3-HDAC4 signaling in the suprachiasmatic nucleus (SCN) regulates circadian period length and timing of arousal: SIK3 deficiency in GABAergic/NMS neurons delays arousal onset and lengthens circadian period; HDAC4 S245A (resistant to SIK3 phosphorylation) delays arousal; heterozygous HDAC4 deficiency shortens period. Cell-type-specific SIK3 conditional knockout mice, gain-of-function SIK3 mutant induction in GABAergic neurons, HDAC4 S245A knock-in mice, EEG/EMG and circadian behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 36877841
2023 SIK3 forms a complex with HDAC4 in hippocampal neurons, directly phosphorylates HDAC4, and regulates its nucleocytoplasmic shuttling to control expression of synaptic plasticity-related genes via MEF2C and histone deacetylase recruitment; SIK3 deletion accelerates cognitive deterioration in an AD mouse model. Co-immunoprecipitation, western blotting, ChIP-qPCR, immunofluorescence for HDAC4 localization, conditional hippocampal SIK3 deletion, electrophysiology Neuropsychopharmacology Medium 38057370
2025 The human NSS SIK3-N783Y mutation results in diminished kinase activity in vitro and, in a mouse knock-in model, decreases sleep time while increasing EEG delta power; at the phosphoproteomic level, this mutation induces changes predominantly at synaptic sites and alters PKA and MAPK signaling networks. In vitro kinase activity assay, knock-in mouse model, EEG/EMG analysis, phosphoproteomics Proceedings of the National Academy of Sciences of the United States of America High 40324078
2024 SIK3 conditional knockout in osteoclasts leads to increased bone mass and an osteopetrosis phenotype; SIK3 deletion and pterosin B treatment inhibit osteoclast differentiation and reduce resorption activity, with alterations in TCA cycle and oxidative phosphorylation metabolism. Osteoclast-specific SIK3 conditional knockout mice, in vitro osteoclast differentiation assay, pterosin B pharmacology, gene expression analysis, metabolic pathway analysis Journal of bone and mineral research Medium 39030684
2023 In Drosophila, Wnk kinase phosphorylates Fray (a transcriptional target of the SIK3 K+ buffering program) in glia, and this converges with SIK3-dependent transcriptional regulation to control Na+/K+/Cl- co-transporter activity, K+ buffering, and seizure susceptibility. Drosophila genetics (SIK3 pathway upregulation, Wnk manipulations), electrophysiology, seizure behavioral assays, cell-type-specific expression of constitutively active Fray PLoS genetics Medium 36626385
2024 SIK3 granulosa cell-specific knockout results in infertility, gonadotropin insensitivity, reduced estradiol, fewer antral follicles, increased apoptosis, and decreased proliferation in follicles, demonstrating SIK3 is required for normal granulosa cell function and follicle development. Granulosa cell-specific SIK3 conditional knockout (Cyp19a1pII-Cre x SIK3-floxed), hormone assays, superovulation, histology, apoptosis/proliferation staining Endocrinology Medium 39158086

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1987 The primary structure of rat ribosomal protein L19. A determination from the sequence of nucleotides in a cDNA and from the sequence of amino acids in the protein. The Journal of biological chemistry 152 3542997
2015 Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer immunology, immunotherapy : CII 150 25971540
2010 The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma. European journal of cancer (Oxford, England : 1990) 149 20797845
2011 A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 126 22028492
2008 Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood 122 19005180
2019 The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC. Cancer discovery 119 31350328
1993 High-level expression of the ribosomal protein L19 in human breast tumors that overexpress erbB-2. Cancer research 102 8095182
1983 The nucleotide sequence of an Escherichia coli operon containing genes for the tRNA(m1G)methyltransferase, the ribosomal proteins S16 and L19 and a 21-K polypeptide. The EMBO journal 98 6357787
2005 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK. Journal of cell science 94 16306228
2014 Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects. Clinical cancer research : an official journal of the American Association for Cancer Research 86 25552483
2013 The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases. The Journal of biological chemistry 83 23393134
2014 Intralesional treatment of stage III metastatic melanoma patients with L19-IL2 results in sustained clinical and systemic immunologic responses. Cancer immunology research 81 24906352
2012 Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. Journal of cancer research and clinical oncology 81 23160853
2016 Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. Nature communications 76 27009967
2006 Radioimmunotherapy of head and neck cancer xenografts using 131I-labeled antibody L19-SIP for selective targeting of tumor vasculature. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 76 16818947
2012 SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice. Development (Cambridge, England) 74 22318228
2015 Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila. PLoS genetics 73 25996931
2008 The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 70 18676770
1977 Isolation of eukaryotic ribosomal proteins. Purification and characterization of 60 S ribosomal subunit proteins L3, L6, L7', L8, L10, L15, L17, L18, L19, L23', L25, L27', L28, L29, L31, L32, L34, L35, L36, L36', and L37'. The Journal of biological chemistry 68 863909
2012 Involvement of SIK3 in glucose and lipid homeostasis in mice. PloS one 67 22662228
2012 Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma. Journal of surgical oncology 67 22674435
2016 Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. The Biochemical journal 63 27920213
2018 Parathyroid hormone(1-34) and its analogs differentially modulate osteoblastic Rankl expression via PKA/SIK2/SIK3 and PP1/PP2A-CRTC3 signaling. The Journal of biological chemistry 57 30377251
2018 A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice. Proceedings of the National Academy of Sciences of the United States of America 56 30254177
2020 Berberine and Emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 52 32682817
2006 Compensatory evolution reveals functional interactions between ribosomal proteins S12, L14 and L19. Journal of molecular biology 48 17157877
2020 Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial. BMC cancer 46 32539805
2018 The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses. Oncoimmunology 44 29632732
2018 The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling. Science translational medicine 43 30232230
2008 Comparative immunohistochemistry of L19 and F16 in non-small cell lung cancer and mesothelioma: two human antibodies investigated in clinical trials in patients with cancer. Lung cancer (Amsterdam, Netherlands) 43 18799229
2021 Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19-IL2 cures poorly immunogenic tumors when combined with radiotherapy. Journal for immunotherapy of cancer 38 33688020
2017 Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation. PloS one 38 28658303
1995 The L19 ribosomal protein gene (RPL19): gene organization, chromosomal mapping, and novel promoter region. Genomics 36 7789970
2014 Ribosomal protein L19 overexpression activates the unfolded protein response and sensitizes MCF7 breast cancer cells to endoplasmic reticulum stress-induced cell death. Biochemical and biophysical research communications 35 24950402
1978 A transducing lambda phage carrying grpE, a bacterial gene necessary for lambda DNA replication, and two ribosomal protein genes, rpsP (S16) and rplS (L19). Molecular & general genetics : MGG 34 368561
2018 A novel anti-cancer L19-interleukin-12 fusion protein with an optimized peptide linker efficiently localizes in vivo at the site of tumors. Journal of biotechnology 32 30586544
2015 Combination of radiotherapy with the immunocytokine L19-IL2: Additive effect in a NK cell dependent tumour model. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 30 26138057
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
2007 Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models. British journal of cancer 29 17519905
2014 Salt-inducible kinase 3, SIK3, is a new gene associated with hearing. Human molecular genetics 27 25060954
2017 SIK3-HDAC4 signaling regulates Drosophila circadian male sex drive rhythm via modulating the DN1 clock neurons. Proceedings of the National Academy of Sciences of the United States of America 25 28743754
1990 Nucleotide sequence of mouse L19 ribosomal protein cDNA isolated in screening with tre oncogene probes. DNA and cell biology 24 1702292
2017 Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock. Critical care (London, England) 23 28270177
2015 Targeting Syndecan-1, a molecule implicated in the process of vasculogenic mimicry, enhances the therapeutic efficacy of the L19-IL2 immunocytokine in human melanoma xenografts. Oncotarget 23 26460958
1992 Human cDNAs encoding elongation factor 1 gamma and the ribosomal protein L19. Nucleic acids research 23 1598220
1981 Characterization of the binding of rat liver ribosomal proteins L6, L8, L19, S9, and S13 to 5.8 S ribosomal ribonucleic acid. The Journal of biological chemistry 22 7251593
1980 Characterization of the binding of rat liver ribosomal proteins L6, L7, and L19 to 5 S ribosomal ribonucleic acid. The Journal of biological chemistry 22 7400140
2018 Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model. Journal of cancer research and clinical oncology 21 29327244
2016 FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19. Journal of industrial microbiology & biotechnology 21 27757551
2019 L19-IL2 Immunocytokine in Combination with the Anti-Syndecan-1 46F2SIP Antibody Format: A New Targeted Treatment Approach in an Ovarian Carcinoma Model. Cancers 20 31443604
2009 Identification of ribosomal protein L19 as a novel tumor antigen recognized by autologous cytotoxic T lymphocytes in lung adenocarcinoma. Cancer science 20 19799608
2023 SIK3-HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice. Proceedings of the National Academy of Sciences of the United States of America 19 36877841
2020 Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study. International journal of radiation oncology, biology, physics 19 33285270
2024 Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases. Journal of medicinal chemistry 18 38552030
2020 The immunocytokine L19-TNF eradicates sarcomas in combination with chemotherapy agents or with immune check-point inhibitors. Anti-cancer drugs 16 32304410
1984 The localization of protein L19 on the surface of 50 S subunits of Escherichia coli aided by the use of mutants lacking protein L19. The Journal of biological chemistry 16 6423642
1980 Purification of Drosophila ribosomal proteins. Isolation of proteins S8, S13, S14, S16, S19, S20/L24, S22/L26, S24, S25/S27, S26, S29, L4, L10/L11, L12, L13, L16, L18, L19, L27, 1, 7/8, 9, and 11. Biochemistry 16 6773542
2015 Long-lasting antitumor effects provided by radiotherapy combined with the immunocytokine L19-IL2. Oncoimmunology 15 26405576
2019 Association of BUD13-ZNF259-APOA5-APOA1-SIK3 cluster polymorphism in 11q23.3 and structure of APOA5 with increased plasma triglyceride levels in a Korean population. Scientific reports 14 31165758
1978 Genes encoding ribosomal proteins S16 and L19 form a gene cluster at 56.4 min in Escherichia coli. Molecular & general genetics : MGG 14 368562
2021 Induction of Mutant Sik3 Allele in Neurons in Late Infancy Increases Sleep Need. The Journal of neuroscience : the official journal of the Society for Neuroscience 13 33558433
2019 Changes in acetyl-CoA mediate Sik3-induced maturation of chondrocytes in endochondral bone formation. Biochemical and biophysical research communications 13 31280862
2019 Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade. Oncotarget 13 31803362
2015 Directed evolution of nitrilase PpL19 from Pseudomonas psychrotolerans L19 and identification of enantiocomplementary mutants toward mandelonitrile. Biochemical and biophysical research communications 13 26577409
2023 Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 12 38057370
2017 Potential anticancer effect of prostratin through SIK3 inhibition. Oncology letters 12 29435066
2019 SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water. The Journal of cell biology 11 31645458
1978 Primary structure of protein L19 from the large subunit of Escherichia coli ribosomes. Biochemistry 11 339951
1994 Analysis of a 17.4 kb DNA segment of yeast chromosome II encompassing the ribosomal protein L19 as well as proteins with homologies to components of the hnRNP and snRNP complexes and to the human proliferation-associated p120 antigen. Yeast (Chichester, England) 9 7725803
1993 Cross-linked amino acids in the protein pairs L3-L19 and L23-L29 of Bacillus stearothermophilus ribosomes after treatment with diepoxybutane. The Journal of biological chemistry 9 8444837
2011 Ribosomal Protein L19 and L22 Modulate TLR3 Signaling. Immune network 8 21860608
2011 The ribosomal protein L19 mRNA is induced by copper exposure in the swordtail fish, Xiphophorus helleri. Molecular biology reports 8 21956757
2014 Structure and gene cluster of the O antigen of Escherichia coli L-19, a candidate for a new O-serogroup. Microbiology (Reading, England) 7 25061042
2010 Fecal RNA detection of cytokeratin 19 and ribosomal protein L19 for colorectal cancer. Hepato-gastroenterology 7 21033215
2025 Staphylococcus aureus blocks host autophagy through circSyk/miR-5106/Sik3 axis to promote progression of bone infection. PLoS pathogens 6 39869636
2022 Biochemical purification uncovers mammalian sterile 3 (MST3) as a new protein kinase for multifunctional protein kinases AMPK and SIK3. The Journal of biological chemistry 6 35413286
2014 Characterization of the pattern of ribosomal protein L19 production during the lifecycle of Leishmania spp. Experimental parasitology 6 25290356
2025 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 5 40324078
2024 Impact of the SIK3 pathway inhibition on osteoclast differentiation via oxidative phosphorylation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 5 39030684
2023 SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility. PLoS genetics 4 36626385
2016 Alterations in ribosomal protein L19 that decrease the fidelity of translation. Biochimie 4 27477481
1995 Nucleotide sequence and characterization of the Saccharomyces cerevisiae RPL19A gene encoding a homolog of the mammalian ribosomal protein L19. Yeast (Chichester, England) 4 7785339
2023 Face validation and pharmacologic analysis of Sik3Sleepy mutant mouse as a possible model of idiopathic hypersomnia. European journal of pharmacology 3 37356786
2023 A phosphorylation-deficient mutant of Sik3, a homolog of Sleepy, alters circadian sleep regulation by PDF neurons in Drosophila. Frontiers in neuroscience 3 37662102
2022 Contribution of APOA5, APOC3, CETP, ABCA1 and SIK3 genetic variants to hypertriglyceridemia development in Mexican HIV-patients receiving antiretroviral therapy. Pharmacogenetics and genomics 3 34693928
2025 Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor. Journal of medicinal chemistry 2 40711360
2023 The AMPK-like protein kinases Sik2 and Sik3 interact with Hipk and induce synergistic tumorigenesis in a Drosophila cancer model. Frontiers in cell and developmental biology 2 37854071
2021 [Analysis of SIK3 gene variation in a boy with autism spectrum disorder complicated with epilepsy]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 34839513
2010 A new bioassay for the immunocytokine L19-IL2 for simultaneous analysis of both functional moieties. Journal of pharmaceutical and biomedical analysis 2 20828971
1990 The mammalian genome contains a high proportion of processed pseudogenes corresponding to ribosomal protein L19. Biochemistry international 2 2099152
2025 EFHD1 Activates SIK3 to Limit Colorectal Cancer Initiation and Progression via the Hippo Pathway. Journal of Cancer 1 39895792
2024 SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo. Endocrinology 1 39158086
2023 Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAAR α1 Expression. Molecular neurobiology 1 37715891
2026 Dexmedetomidine Alleviates Sleep Rhythm Abnormalities in Chronic Sleep-Deprived Mice via Modulation of SIK3/HDAC4/5 Signalling. Clinical and experimental pharmacology & physiology 0 41271199
2026 Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes. JCI insight 0 41657312
2026 Molecular mechanisms of T221 phosphorylation in modulating SIK3 kinase function and ATP binding. Physical chemistry chemical physics : PCCP 0 41948837
2026 Evaluating Ribosomal Protein L19 mRNA as a Biomarker in Ulcerative Colitis: Implications for Severity Assessment. Mediators of inflammation 0 42033356
2025 Trypanosoma brucei L19 is essential for ribosomal function. Biochemical and biophysical research communications 0 40117972
2025 Sleeping less with a SIK3 mutation. Trends in genetics : TIG 0 40610343
2019 Glial SIK3: A central player in ion and volume homeostasis in Drosophila peripheral nerves. The Journal of cell biology 0 31723008