Affinage

SIK2

Serine/threonine-protein kinase SIK2 · UniProt Q9H0K1

Length
926 aa
Mass
103.9 kDa
Annotated
2026-06-10
93 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIK2 is a serine/threonine kinase of the AMPK/SNF1 family that integrates hormonal, metabolic, and stress cues to control transcription, organelle dynamics, autophagy, and the cell cycle (PMID:11027514, PMID:21220102). Its best-defined output is repression of CREB-driven transcription: SIK2 phosphorylates the CRTC/TORC coactivators (CRTC1/2/3) to retain them in the cytoplasm and phosphorylates class IIa HDACs (HDAC4/5/7/9) to promote their 14-3-3 binding and nuclear export, thereby tuning CREB- and MEF2-dependent gene programs (PMID:21220102, PMID:23393134, PMID:25472719). This kinase activity is gated by PKA, which phosphorylates SIK2 at Ser358 and Ser587 to drive 14-3-3 binding and relocalization and to release CRTC/PP2A from SIK2, and by additional inputs including CaMK I/IV-mediated Thr484 phosphorylation that triggers SIK2 degradation, insulin-induced Thr484 stabilization, and reversible acetylation at Lys53 (inhibitory p300/CBP acetylation reversed by HDAC6) (PMID:22462548, PMID:25472719, PMID:21220102, PMID:23322770, PMID:30586628). Through these axes SIK2 governs metabolic homeostasis—glucose uptake and GLUT4 levels, lipogenic and ketogenic gene expression, and β-cell insulin secretion via the SIK2–p35–PJA2 module (PMID:24898145, PMID:25472719, PMID:24561619, PMID:26983400). Beyond transcription, SIK2 localizes to centrosomes where it controls centrosome separation and mitotic progression, phosphorylates p97/VCP at the ER to drive ERAD, and acts in autophagy through GABARAPL2 Ser72 phosphorylation to enable autophagosome–lysosome fusion (PMID:20708153, PMID:24129571, PMID:41126299). SIK2 additionally phosphorylates a broad substrate set linking it to motility (MYLK Ser343), mitochondrial fission (Drp1 Ser616), Wnt activation (LRP6), negative feedback on FGF/ERK signaling (Gab1 Ser266), and DNA double-strand break repair, and is itself targeted for degradation by Fbxw7 and the CUL4B–DDB1 complex (PMID:35278271, PMID:31639424, PMID:35277657, PMID:39267218, PMID:35642638, PMID:32437091, PMID:42213109).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 Medium

    Established SIK2 as a catalytically active serine/threonine kinase of the AMPK/SNF1 family, defining the protein class before any substrate was known.

    Evidence In vitro autophosphorylation kinase assay following gene identification by representational difference analysis

    PMID:11027514

    Open questions at the time
    • No physiological substrate identified
    • No upstream activating kinase defined
    • Foundational single study
  2. 2010 High

    Defined the core SIK2 transcriptional axis—suppression of CRTC/TORC nuclear translocation to repress CREB-target genes—and linked it to a physiological output (melanogenesis) and to centrosome biology in mitosis.

    Evidence Sik2-/- mice (agouti background pigmentation; centrosome phenotypes), C-Nap1 phosphosite mapping, siRNA mitotic readouts, xenografts

    PMID:20708153 PMID:20819186

    Open questions at the time
    • Whether centrosomal and transcriptional roles share regulatory inputs unresolved
    • Direct in vivo CRTC phosphosite occupancy not mapped in melanocytes
  3. 2011 High

    Showed SIK2 abundance itself is a regulated node: CaMK I/IV phosphorylation at Thr484 drives SIK2 degradation, relieving CRTC1 repression to promote CREB-dependent neuronal survival.

    Evidence In vitro CaMK kinase assay, sik2-/- neurons under oxygen-glucose deprivation, transient focal ischemia model

    PMID:21220102

    Open questions at the time
    • Identity of the degradation machinery acting after Thr484 phosphorylation not defined here
    • Generalizability beyond ischemic neurons untested
  4. 2013 High

    Expanded the SIK2 substrate repertoire beyond CRTCs to class IIa HDACs, p97/VCP, and p300, and revealed acetylation as a direct regulator of kinase activity—connecting SIK2 to MEF2 transcription, ERAD, and autophagy.

    Evidence In vitro kinase and 14-3-3 binding assays, ATPase assays, ERAD substrate degradation, acetylation-mimetic mutagenesis, autophagy flux assays

    PMID:23322770 PMID:23393134 PMID:24129571

    Open questions at the time
    • Whether HDAC, VCP, and CRTC branches are co-regulated or context-segregated unclear
    • Acetylation dynamics in vivo not established
  5. 2014 High

    Connected SIK2 to whole-body metabolic control and β-cell function, defining the SIK2–p35–PJA2 ubiquitylation module for insulin secretion and CRTC2-CREB-dependent adipose/muscle glucose handling, plus a cardiac hypertrophy role.

    Evidence β-cell-specific and global Sik2-/- mice, in vitro p35 Ser91 kinase and ubiquitylation assays, metabolic phenotyping, high-salt cardiac model

    PMID:24561619 PMID:24752134 PMID:24898145

    Open questions at the time
    • Tissue-specific upstream activators differ and are incompletely mapped
    • Relationship between secretory and transcriptional metabolic roles not unified
  6. 2012 High

    Mechanistically resolved PKA control of SIK2: Ser358 phosphorylation creates a 14-3-3 binding site driving cytosolic relocalization, providing the molecular basis for cAMP-dependent inhibition of SIK2 function.

    Evidence Phosphopeptide mapping, Ser358Ala mutagenesis, 14-3-3 binding and adipocyte fractionation

    PMID:22462548

    Open questions at the time
    • How relocalization couples to substrate selection not defined
    • Role of additional PKA sites left open
  7. 2015 Medium

    Showed PKA Ser358 phosphorylation simultaneously releases CRTC and PP2A from SIK2, integrating multiple substrate/regulator interactions into one regulated complex controlling GLUT4 and glucose uptake; also identified B55gamma as a stabilizing partner.

    Evidence Reciprocal Co-IP (CRTC2/3, HDAC4, PP2A, B55gamma), siRNA, glucose uptake assays in human adipocytes and glioma

    PMID:25472719 PMID:25792973

    Open questions at the time
    • Stoichiometry and assembly order of the SIK2-PP2A-CRTC complex unknown
    • B55gamma stabilization mechanism not structurally defined
  8. 2016 High

    Extended SIK2 substrate-level control to lipid/ketone metabolism (p300 Ser89 disrupting PPARα), autophagy restraint in breast cancer, and isoform-resolved macrophage polarization, broadening SIK2 from a transcriptional regulator to a hub over metabolism, cell death, and immunity.

    Evidence In vitro p300 kinase assay and S89A mutagenesis, ATG5-rescue epistasis, catalytically-inactive SIK2/SIK3 knock-in mice with IL-10 readouts

    PMID:26983400 PMID:27697861 PMID:27920213

    Open questions at the time
    • Functional redundancy versus specificity between SIK2 and SIK3 incompletely parsed
    • How SIK2 both restricts and later promotes autophagy across contexts unresolved
  9. 2018 Medium

    Clarified divergent inputs to Thr484: insulin phosphorylation stabilizes SIK2 without altering catalytic activity, contrasting with the degradative CaMK signal, and PKA Ser587 was tied to sleep regulation.

    Evidence Thr484 phospho-specific antibody and kinase assays in primary adipocytes; Sik2S587A knock-in EEG sleep recordings; osteoblast PTH-CRTC-RANKL siRNA epistasis

    PMID:30377251 PMID:30586628 PMID:32457359

    Open questions at the time
    • How identical Thr484 site yields opposite stability outcomes depending on signal unresolved
    • Direct substrate(s) underlying sleep phenotype not identified
  10. 2022 High

    Identified direct kinase-substrate relationships driving cancer phenotypes—MYLK Ser343 for motility/metastasis and LRP6 for Wnt/β-catenin and stemness—and linked SIK2-HDAC-MEF2D signaling to DNA double-strand break repair gene expression.

    Evidence In vitro kinase assays with phosphosite mutagenesis, kinase-dead/inhibitor validation, ChIP/ATAC-seq, DSB repair and metastasis assays

    PMID:35277657 PMID:35278271 PMID:35642638

    Open questions at the time
    • Whether centrosomal and DNA-repair roles converge mechanistically unclear
    • In vivo therapeutic windows for SIK2 inhibition not defined here
  11. 2024 High

    Defined GABARAPL2 Ser72 as a direct SIK2 substrate enabling autophagosome-lysosome fusion with protective effects in Alzheimer's models, and Gab1 Ser266 phosphorylation as a negative-feedback brake on FGF2/ERK signaling, while CUL4B-DDB1 (via K144) was identified as a degradation route.

    Evidence Phosphoproteomics, S72E/S72A and S266 mutagenesis, AAV delivery and behavioral/LTP assays, in vitro Gab1 kinase assay, MS identification of CUL4B-DDB1 with K144 mutagenesis

    PMID:39267218 PMID:41126299 PMID:42213109

    Open questions at the time
    • How SIK2 selects between autophagy-promoting and autophagy-restricting roles across tissues unresolved
    • Upstream signals controlling CUL4B-DDB1-mediated SIK2 turnover unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single kinase coordinates its many spatially distinct functions—centrosomal mitotic control, ER-associated ERAD, autophagosome fusion, and nuclear transcriptional repression—and what determines substrate selection under competing PKA, CaMK, insulin, and acetylation inputs.
  • No unified model of how regulatory inputs route SIK2 to specific substrate pools
  • Structural basis of substrate discrimination unknown
  • Context-dependent pro- versus anti-autophagic roles unreconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 5 GO:0140657 ATP-dependent activity 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 2 R-HSA-168256 Immune System 1
Partners
CRTC2CUL4BFBXW7HDAC4P35/CDK5R1P97/VCPPJA2PP2A

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 SIK2 localizes at the centrosome and regulates centrosome linker protein C-Nap1 localization through phosphorylation of C-Nap1 at Ser2392. PKA (a known SIK2 inhibitor) induces SIK2-dependent centrosome splitting in interphase, while SIK2 depletion blocks centrosome separation in mitosis and reduces AKT phosphorylation. Immunofluorescence localization, phosphorylation mapping by mutagenesis, siRNA depletion with mitotic phenotype readout, xenograft studies Cancer cell High 20708153
2011 SIK2 phosphorylates and suppresses TORC1 (CRTC1) nuclear translocation, thereby repressing CREB-mediated gene expression in neurons. During oxygen-glucose deprivation, CaMK I/IV phosphorylate SIK2 at Thr484, leading to SIK2 protein degradation and consequent TORC1 dephosphorylation and CREB activation, promoting neuronal survival. In vitro kinase assay (CaMK phosphorylation of SIK2), sik2−/− mouse neurons with OGD survival assay, transient focal ischemia model, immunoblotting for TORC1 phosphorylation Neuron High 21220102
2010 SIK2 suppresses TORC1 nuclear translocation and CREB-mediated Mitf gene expression in melanocytes, thereby repressing eumelanogenesis. In vivo, Sik2−/− mice on an agouti (Ay/a) background showed brown hair, demonstrating that SIK2 represses eumelanogenesis. B16 melanoma cell overexpression/KO, UV-induced TORC1 nuclear translocation assay, Sik2−/− mouse genetics with Ay/a background, hair pigmentation analysis Pigment cell & melanoma research High 20819186
2013 LKB1 activates SIK2 (and SIK3), which then phosphorylates class IIa HDACs (HDAC4, -5, -7, -9) at conserved motifs to promote 14-3-3 binding and nuclear export. SIK2 activates MEF2-dependent transcription and relieves repression of myogenesis by the HDACs. This pathway is PKA-sensitive. In vitro kinase assay, 14-3-3 binding assay, subcellular fractionation, MEF2 reporter assay, myogenesis assay The Journal of biological chemistry High 23393134
2013 SIK2 kinase activity is regulated by reversible acetylation: p300/CBP-mediated acetylation at Lys-53 inhibits SIK2 kinase activity, whereas HDAC6-mediated deacetylation restores it. The acetylation-mimetic SIK2-K53Q mutant causes autophagosome accumulation, while SIK2 knockdown abrogates autophagosome-lysosome fusion and impairs TDP-43Δ inclusion body clearance. In vitro kinase assay, acetylation-mimetic and non-acetylatable mutagenesis, autophagosome accumulation assay, lysosome fusion assay, siRNA knockdown The Journal of biological chemistry High 23322770
2013 SIK2 physically interacts with p97/VCP (co-localized at ER membrane) and phosphorylates p97/VCP to stimulate its ATPase activity, thereby promoting degradation of ERAD substrates. Kinase-deficient SIK2 or knockdown impairs ERAD substrate degradation and disrupts ER homeostasis. Co-immunoprecipitation, co-localization by immunofluorescence, in vitro ATPase activity assay, ERAD substrate degradation assay, kinase-dead mutant analysis, siRNA knockdown The Journal of biological chemistry High 24129571
2014 SIK2 forms a complex with CDK5 activator p35 and E3 ligase PJA2 in pancreatic β-cells. Following glucose stimulation, SIK2 phosphorylates p35 at Ser91, triggering p35 ubiquitylation by PJA2 and promoting insulin secretion. β-cell-specific SIK2 knockout leads to p35 accumulation and impaired insulin secretion. Co-immunoprecipitation, in vitro kinase assay (SIK2 phosphorylation of p35 at Ser91), ubiquitylation assay, β-cell-specific KO mouse with insulin secretion phenotype, mass spectrometry for complex identification Nature cell biology High 24561619
2014 SIK2 KO mice exhibit increased CRTC2-CREB transcriptional activity in white adipocytes, elevated ATF3, reduced GLUT4 expression, reduced glucose uptake in muscle and adipocytes, hypertriglyceridemia due to increased lipolysis, and impaired glucose and insulin tolerance. SIK2 KO mouse metabolic phenotyping, glucose/insulin tolerance tests, lipolysis assays, CRTC2-CREB pathway analysis, 3T3-L1 adipocyte culture, CRTC2 KO comparison Diabetes High 24898145
2012 PKA phosphorylates SIK2 at Ser358 in adipocytes in response to cAMP elevation (e.g., forskolin, β-adrenergic agonist), promoting 14-3-3 binding and a phosphorylation-dependent relocalization of SIK2 from a particulate fraction to the cytosol. Ser358Ala mutation abolishes 14-3-3 binding and relocalization. Phosphopeptide mapping of SIK2, site-directed mutagenesis (Ser358Ala), 14-3-3 binding assay, adipocyte fractionation, immunocytochemistry The Biochemical journal High 22462548
2015 In adipocytes, SIK2 directly phosphorylates CRTC2, CRTC3, and HDAC4. CRTC2, CRTC3, HDAC4, and PP2A all interact with SIK2. PKA-mediated phosphorylation of SIK2 at Ser358 reduces binding of CRTCs and PP2A to SIK2. SIK2 increases GLUT4 protein levels and glucose uptake in adipocytes through this pathway. Co-immunoprecipitation (SIK2 with CRTC2/3, HDAC4, PP2A), siRNA knockdown of SIK2/CRTC2/HDAC4, GLUT4 protein measurement, glucose uptake assay, SIK2 overexpression and pharmacological inhibition Journal of cell science High 25472719
2008 SIK2 is activated in 3T3-L1 adipocytes by nutrient deprivation, ATP synthesis inhibition, and AICAR treatment. SIK2 overexpression represses lipogenic gene expression (FAS, ACC2, SCD1) by reducing SREBP-1 nuclear translocation, independent of AMPK; knockdown increases these genes. In vitro kinase activity assay (peptide substrate phosphorylation), adenovirus-mediated overexpression and siRNA knockdown, FAS promoter-luciferase reporter, SREBP-1 nuclear translocation by immunoblot Obesity (Silver Spring, Md.) High 18239551
2016 SIK2 restricts autophagic flux in triple-negative breast cancer cells. Genetic or pharmacological inhibition of SIK2 increases autophagic flux and selectively causes cell death in breast cancer cells (especially claudin-low subtype). Depletion of ATG5 rescues viability loss after SIK2 inhibition, placing SIK2 upstream of autophagosome formation. Loss-of-function screening, siRNA/pharmacological SIK2 inhibition, autophagic flux assay, ATG5 depletion rescue, in vivo tumor growth assay Molecular and cellular biology High 27697861
2016 SIK2 and SIK3 contribute to macrophage polarization. Knock-in of catalytically inactive SIK2 and SIK3 in mice demonstrated that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhances IL-10 production and produces a stable anti-inflammatory macrophage phenotype even after kinase reactivation. Knock-in mice expressing catalytically inactive SIK1, SIK2, SIK3; primary macrophage cytokine production assays; pharmacological inhibition during differentiation The Biochemical journal High 27920213
2016 SIK2 phosphorylates p300 at Ser89, disrupting p300-PPARα interaction (which normally occurs via a conserved LXXLL motif on p300) and thereby decreasing PPARα-mediated ketogenic gene expression. The phosphorylation-defective p300 S89A mutant shows increased PPARα interaction and abolishes SIK2 suppression of ketogenesis. In vitro kinase assay (SIK2 phosphorylation of p300), co-immunoprecipitation (p300-PPARα interaction), site-directed mutagenesis (p300 S89A), ketogenic gene expression assay in liver Scientific reports High 26983400
2018 PTH(1-34) activates PKA, which inhibits SIK2 and SIK3 in osteoblasts, leading to nuclear translocation of CRTC2 and CRTC3 and upregulation of RANKL transcription. Knockdown of SIK2 and SIK3, and PP1/PP2A inhibition, demonstrated that SIK2/3 and protein phosphatases 1/2A are part of the PTH-CRTC2/3-RANKL regulatory pathway. siRNA knockdown of SIK2/3 and CRTCs in primary calvarial osteoblasts, PP1/PP2A inhibitor experiments, RANKL qPCR, CRTC nuclear localization by immunofluorescence The Journal of biological chemistry High 30377251
2019 SIK2 promotes mitochondrial fission through phosphorylation of Drp1 at Ser616, thereby inhibiting mitochondrial oxidative phosphorylation. SIK2 also upregulates HIF-1α by activating the PI3K/AKT signaling pathway, which directly upregulates glycolytic gene transcription (Warburg effect) in ovarian cancer cells. SIK2 overexpression/knockdown, phospho-specific immunoblotting for Drp1-pSer616, PI3K/AKT pathway analysis, mitochondrial function assays, glycolysis assays Cancer letters Medium 31639424
2020 SIK2 promotes lipid synthesis in ovarian cancer by upregulating SREBP1c (and thus FASN) and SREBP2 (and thus HMGCR) through the PI3K/Akt signaling pathway, increasing both fatty acid and cholesterol synthesis. SIK2 knockdown/overexpression, SREBP1c/SREBP2 expression assays, PI3K/Akt pathway inhibition, in vitro and in vivo lipid synthesis assays Cell death & disease Medium 31932581
2020 SIK2 suppresses gastric cancer cell migration/invasion by phosphorylating and activating mTORC1, which inhibits autophagic degradation of protein phosphatases PHLPP2 and PP2A. The upregulated PHLPP2 and PP2A then dephosphorylate and inactivate AKT, thereby inhibiting AKT/GSK3β/β-catenin signaling and EMT. SIK2 overexpression/knockdown, mTORC1 phosphorylation assay, autophagy flux assay, PHLPP2/PP2A protein stability assay, AKT phosphorylation by immunoblot, migration/invasion assay Molecular oncology Medium 33128264
2020 Fbxw7 targets SIK2 for proteasomal degradation by binding the 'TPPPS' motif of SIK2. Endogenous Fbxw7 downregulates SIK2 protein level to control cell cycle progression, interfering with the SIK2/TORC2/AKT signaling pathway and modulating p21 expression. Co-immunoprecipitation (Fbxw7-SIK2 interaction), motif mutation analysis, ubiquitination assay, SIK2 half-life measurement, cell cycle analysis Cell biology international Medium 32437091
2021 SIK2 is recruited to the Salmonella-containing vacuole (SCV) together with the Arp2/3 complex and formins during Salmonella infection. Under basal conditions, SIK2 associates with actin filaments. SIK2 depletion causes a severe actin nucleation and polymerization defect at the SCV, promotes bacterial escape from the SCV, and impairs xenophagy. Global host phosphoproteome analysis post-infection, SIK2 siRNA depletion, immunofluorescence localization to SCV and actin, bacterial survival/proliferation assay, xenophagy assay Proceedings of the National Academy of Sciences of the United States of America High 33947818
2021 ARN-3236 (SIK2 inhibitor) produces antidepressant-like effects in mice via the hippocampal CRTC1-CREB-BDNF pathway. SIK2 inhibition prevents cytoplasmic sequestration of CRTC1 and restores BDNF expression; hippocampal CRTC1 mediates these effects as demonstrated by viral gene transfer. Chronic stress mouse models (CSDS, CUMS), stereotactic viral-mediated gene transfer of CRTC1, co-immunoprecipitation, immunofluorescence, western blotting Frontiers in pharmacology Medium 33519490
2022 SIK2 directly phosphorylates MYLK (myosin light chain kinase, smooth muscle) at Ser343, activating MYLK which then phosphorylates its downstream effector MYL2 (myosin light chain 2), thereby promoting ovarian cancer cell motility and metastasis. Adipocytes induce both SIK2 phosphorylation at Ser358 and MYLK phosphorylation at Ser343. In vitro kinase assay (SIK2 phosphorylating MYLK at Ser343), phospho-specific immunoblotting, Co-immunoprecipitation, siRNA knockdown, cell motility/migration assays, in vivo metastasis model Molecular oncology High 35278271
2022 SIK2 inhibitors decrease phosphorylation of class-IIa HDACs (HDAC4/5/7) and abolish HDAC4/5/7-associated transcriptional activity of MEF2D, decreasing MEF2D binding to regulatory regions of FANCD2, EXO1, and XRCC4 genes, resulting in repression of DNA double-strand break repair. SIK2 inhibition also decreases PARP enzyme activity. SIK2 inhibitors (ARN3236, ARN3261) in cancer cells, HDAC4/5/7 phosphorylation immunoblotting, MEF2D chromatin accessibility (ATAC-seq), MEF2D ChIP at target gene loci, DNA DSB repair assays, PARP activity assay, xenograft studies The Journal of clinical investigation High 35642638
2022 SIK2 inhibition by ARN-3236 prevents fibroblast differentiation and reduces extracellular matrix expression. Mechanistically, SIK2 inactivation results in dephosphorylation and nuclear translocation of CRTC2, which then binds CREB to promote CREB-dependent anti-fibrotic gene expression. Western blot of SIK2/pCRTC2 in fibroblasts, ARN-3236 treatment and siRNA knockdown, CRTC2 nuclear translocation by fractionation, bleomycin mouse model of pulmonary fibrosis, immunohistochemistry BMC pulmonary medicine Medium 35410283
2022 SIK2 overexpression reduces ER stress-mediated tubular epithelial apoptosis by inhibiting the histone acetyltransferase activity of p300, thereby activating HSF1/Hsp70. This mechanism underlies SIK2 protection against diabetic kidney disease. SIK2 KO and overexpression in diabetic mice, transcriptome sequencing, p300 histone acetyltransferase activity assay, HSF1/Hsp70 pathway analysis, ER stress markers Translational research : the journal of laboratory and clinical medicine Medium 36075517
2022 SIK2 directly phosphorylates LRP6, leading to Wnt/β-catenin signaling pathway activation and induction of IDH1 expression in breast cancer stem cells. This phosphorylation is kinase activity-dependent. SIK2 itself is phosphorylated upstream by CK1α. In vitro kinase assay (SIK2 phosphorylation of LRP6), β-catenin accumulation assay, SIK2 kinase-dead mutant analysis, SIK2 inhibitors (ARN-3236, HG-9-91-01) blocking LRP6 phosphorylation, breast cancer stem cell proportion assays, IDH1 expression analysis Oncogene High 35277657
2013 In DLBCL, siRNA-mediated downregulation of SIK2 results in upregulation of the CREB target gene BIM, consistent with SIK2's role in phosphorylating and inhibiting its cofactor TORC2/CRTC2, thereby repressing CREB-mediated transcription. siRNA knockdown of SIK2, RT-PCR for BIM expression, Western blot, cAMP and dexamethasone treatment Leukemia & lymphoma Medium 20367563
2015 B55gamma (PPP2R2C) interacts with and stabilizes SIK2 protein. The B55gamma-SIK2 complex is required for B55gamma-mediated suppression of S6K phosphorylation and promotion of glioma cell survival under glucose starvation. Co-immunoprecipitation (B55gamma-SIK2 interaction), siRNA knockdown of SIK2, S6K phosphorylation assay, cell viability under glucose deprivation Cancer cell international Medium 25792973
2014 SIK2 is required for cardiac left ventricular hypertrophy (LVH) development in response to chronic high-salt diet. Sik2−/− mice do not develop LVH upon high-salt feeding, while wild-type mice do. In cardiac myocytes, α-adducin regulates SIK2 expression, and SIK2 mediates adducin's effects on hypertrophy marker gene activation. Sik2−/− mouse model on high-salt diet, echocardiography (LV wall thickness), gene expression of hypertrophy markers, cardiac myocyte culture with α-adducin manipulation PloS one High 24752134
2020 PKA phosphorylation site Ser587 of SIK2 regulates sleep need. Sik2S587A knock-in mice showed increased NREM sleep delta density, indicating that the PKA-SIK2 signaling axis is involved in regulating sleep. Sik2S587A knock-in mice, EEG/EMG sleep recording (NREM sleep time, delta density), sleep deprivation recovery experiments Scientific reports Medium 32457359
2013 In Müller glia, SIK2 activity increases in response to insulin stimulation and is associated with increased IRS1-SIK2 interaction. SIK2 negatively modulates insulin-dependent cell survival: overexpression reduces pAkt levels while knockdown increases pAkt and reduces apoptosis. Under hyperglycemia, increased SIK2 activity correlates with reduced Akt activation and enhanced apoptosis. In vitro kinase assay (SIK2 activity), co-immunoprecipitation (IRS1-SIK2), siRNA knockdown and overexpression, pAkt immunoblotting, TUNEL apoptosis assay, streptozotocin rat model Investigative ophthalmology & visual science Medium 23599336
2018 Insulin induces phosphorylation of SIK2 at Thr484 in primary adipocytes, which is associated with increased SIK2 protein stability but does not affect SIK2 catalytic activity or its activity towards HDAC4. Phospho-specific antibody for SIK2-Thr484, in vitro kinase assay (no change in activity), SIK2 protein level with MG132 proteasome inhibitor, primary human and rat adipocytes Cellular signalling Medium 30586628
2024 SIK2 phosphorylates GABARAPL2 at Ser72, which is essential for autophagosome-lysosome fusion. The phosphorylation-mimetic GABARAPL2-S72E mutant replicates SIK2-mediated autophagic flux enhancement and reduces Aβ pathology in 5×FAD AD mice, while the non-phosphorylatable S72A mutant fails to show protective effects. Co-immunoprecipitation, GST pull-down, phosphoproteomics, site-directed mutagenesis (S72E, S72A), AAV-mediated hippocampal delivery, mRFP-GFP-LC3 tandem fluorescence autophagy assay, Morris water maze, LTP recording, electron microscopy Translational neurodegeneration High 41126299
2024 SIK2 acts as a negative feedback regulator of FGF2/Ras/ERK1/2 signaling in retinal Müller glia. SIK2 phosphorylates Gab1 at Ser266, which weakens Gab1 interactions with Grb2 and Shp2, thereby downregulating ERK1/2 activation. SIK2 itself is activated downstream of ERK1/2 in an FGF2-dependent manner. In vitro kinase assay (SIK2 phosphorylating Gab1 at Ser266), site-directed mutagenesis, Co-immunoprecipitation (Gab1-Grb2/Shp2), SIK2 overexpression/knockdown with ERK1/2 activation assay Advanced biology High 39267218
2021 SIK2 is synthetic lethal with loss of FANCA. FANCA co-localizes with SIK2 at centrosomes and regulates SIK2 activity at centrosomes. SIK2 depletion in FANCA-deficient cells causes impaired G2-M transition, delayed mitotic progression, cytokinesis failure, and abrogates nocodazole-induced prometaphase arrest, suggesting a role for SIK2 in the spindle assembly checkpoint. Kinome-wide synthetic lethality screen in FANCA-/- fibroblasts, co-localization of FANCA and SIK2 at mitotic structures by immunofluorescence, SIK2 kinase activity assay at centrosomes, pharmacological SIK2 inhibition with cell cycle analysis Molecular oncology Medium 34058059
2024 SIC-19 promotes SIK2 ubiquitination and degradation via the CUL4B-DDB1 E3 ubiquitin ligase complex. Lysine 144 (K144) is the critical ubiquitination site on SIK2 mediating its degradation. CUL4B is functionally required for SIC-19-induced SIK2 degradation. Mass spectrometry identifying ubiquitin ligases binding SIK2, co-immunoprecipitation (SIK2-CUL4B-DDB1), Western blot for SIK2 half-life, site-directed mutagenesis (K144), ubiquitination assay, CUL4B knockdown Molecular and cellular biology High 42213109
2024 SIK2 knockdown in ovarian cancer cells reduces RAD50 phosphorylation at Ser635, prevents nuclear translocation of RAD50, disrupts nuclear filament assembly, and impairs homologous recombination DNA repair, inducing apoptosis. SIK2 siRNA knockdown and SIC-19 inhibitor, phospho-RAD50(Ser635) immunoblotting, RAD50 nuclear localization assay, HR repair functional assay, apoptosis assay Drug resistance updates Medium 38518726
2000 SIK2 (originally named Qik) is a serine-threonine kinase belonging to the AMPK/SNF1 family, capable of autophosphorylation as demonstrated by in vitro kinase assay. In vitro kinase assay (autophosphorylation), representational difference analysis for gene identification Biochemical and biophysical research communications Medium 11027514

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer. Cancer letters 145 31639424
2011 SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron 131 21220102
2010 SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer cell 122 20708153
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 84 23393134
2020 SIK2 enhances synthesis of fatty acid and cholesterol in ovarian cancer cells and tumor growth through PI3K/Akt signaling pathway. Cell death & disease 79 31932581
2015 SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes. Journal of cell science 79 25472719
2022 FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability. International journal of biological sciences 75 36263177
2014 Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation. Nature cell biology 71 24561619
2016 Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. The Biochemical journal 64 27920213
2010 Downregulation of SIK2 expression promotes the melanogenic program in mice. Pigment cell & melanoma research 64 20819186
2014 SIK2 is critical in the regulation of lipid homeostasis and adipogenesis in vivo. Diabetes 61 24898145
2012 The AMPK-related kinase SIK2 is regulated by cAMP via phosphorylation at Ser358 in adipocytes. The Biochemical journal 59 22462548
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 58 30377251
2018 Upregulation of miR-874-3p and miR-874-5p inhibits epithelial ovarian cancer malignancy via SIK2. Journal of biochemical and molecular toxicology 44 30004169
2013 Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy. The Journal of biological chemistry 43 23322770
2008 SIK2 can be activated by deprivation of nutrition and it inhibits expression of lipogenic genes in adipocytes. Obesity (Silver Spring, Md.) 43 18239551
2022 SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers. The Journal of clinical investigation 36 35642638
2022 SIK2 promotes ovarian cancer cell motility and metastasis by phosphorylating MYLK. Molecular oncology 35 35278271
2021 The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway. Frontiers in pharmacology 33 33519490
2016 Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2). Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 33 27236538
2011 A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon (4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells. PloS one 33 22022544
2021 Overexpression of circ_CELSR1 facilitates paclitaxel resistance of ovarian cancer by regulating miR-149-5p/SIK2 axis. Anti-cancer drugs 31 33735118
2020 Long non-coding RNA UCA1 promotes the progression of paclitaxel resistance in ovarian cancer by regulating the miR-654-5p/SIK2 axis. European review for medical and pharmacological sciences 31 32016960
2020 Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need. Scientific reports 31 32457359
2020 SIK2 represses AKT/GSK3β/β-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases. Molecular oncology 31 33128264
2020 CircAMOTL1 Promotes Tumorigenesis Through miR-526b/SIK2 Axis in Cervical Cancer. Frontiers in cell and developmental biology 29 33344445
2021 Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction. Journal of agricultural and food chemistry 28 34735150
2016 SIK2 Restricts Autophagic Flux To Support Triple-Negative Breast Cancer Survival. Molecular and cellular biology 27 27697861
2022 SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. Oncogene 25 35277657
2018 SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways. Oncotarget 25 29774109
2025 SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling. Journal of neuroinflammation 20 41339921
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 19 38552030
2010 Amplification at 11q23 targets protein kinase SIK2 in diffuse large B-cell lymphoma. Leukemia & lymphoma 19 20367563
2019 Parathyroid hormone (PTH) promotes ADSC osteogenesis by regulating SIK2 and Wnt4. Biochemical and biophysical research communications 18 31235257
2023 Discovery of novel and selective SIK2 inhibitors by the application of AlphaFold structures and generative models. Bioorganic & medicinal chemistry 17 37467565
2021 MYBL2-induced PITPNA-AS1 upregulates SIK2 to exert oncogenic function in triple-negative breast cancer through miR-520d-5p and DDX54. Journal of translational medicine 17 34353336
2019 High-Throughput Implementation of the NanoBRET Target Engagement Intracellular Kinase Assay to Reveal Differential Compound Engagement by SIK2/3 Isoforms. SLAS discovery : advancing life sciences R & D 17 31849250
2014 Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake. PloS one 17 24752134
2013 SIK2 is involved in the negative modulation of insulin-dependent muller cell survival and implicated in hyperglycemia-induced cell death. Investigative ophthalmology & visual science 17 23599336
2013 Interaction between salt-inducible kinase 2 (SIK2) and p97/valosin-containing protein (VCP) regulates endoplasmic reticulum (ER)-associated protein degradation in mammalian cells. The Journal of biological chemistry 17 24129571
2021 The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells. Cancers 16 34359562
2020 SIK2 Promotes Cisplatin Resistance Induced by Aerobic Glycolysis in Breast Cancer Cells through PI3K/AKT/mTOR Signaling Pathway. Bioscience reports 16 32458975
2023 LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition. EMBO molecular medicine 14 37966164
2021 Dasatinib-SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations. ACS omega 14 34056256
2021 LINC00662 facilitates osteosarcoma progression via sponging miR-103a-3p and regulating SIK2 expression. Journal of tissue engineering and regenerative medicine 14 34559955
2016 SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300. Scientific reports 14 26983400
2015 The association between Salt-inducible kinase 2 (SIK2) and gamma isoform of the regulatory subunit B55 of PP2A (B55gamma) contributes to the survival of glioma cells under glucose depletion through inhibiting the phosphorylation of S6K. Cancer cell international 14 25792973
2021 The anti-rotavirus effect of baicalin via the gluconeogenesis-related p-JNK-PDK1-AKT-SIK2 signaling pathway. European journal of pharmacology 13 33567320
2023 IGF2BP1 enhances the stability of SIK2 mRNA through m6A modification to promote non-small cell lung cancer progression. Biochemical and biophysical research communications 12 37866243
2022 Drug Repurposing: Escitalopram attenuates acute lung injury by inhibiting the SIK2/ HDAC4/ NF-κB signaling cascade. Biochemical and biophysical research communications 12 35158201
2022 Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice. BMC pulmonary medicine 12 35410283
2022 SIK2 Improving Mitochondrial Autophagy Restriction Induced by Cerebral Ischemia-Reperfusion in Rats. Frontiers in pharmacology 12 35586047
2022 SIK2 protects against renal tubular injury and the progression of diabetic kidney disease. Translational research : the journal of laboratory and clinical medicine 12 36075517
2024 A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 11 38518726
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
2025 Discovery of Novel SIK2/3 Inhibitors for the Potential Treatment of MEF2C+ Acute Myeloid Leukemia (AML). Journal of medicinal chemistry 10 40111261
2021 SIK2 orchestrates actin-dependent host response upon Salmonella infection. Proceedings of the National Academy of Sciences of the United States of America 10 33947818
2023 SIK2: A critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer. The journal of obstetrics and gynaecology research 9 37317594
2020 Tumor-suppressor Fbxw7 targets SIK2 for degradation to interfere with TORC2-AKT signaling in pancreatic cancer. Cell biology international 9 32437091
2000 The new serine-threonine kinase, Qik, is a target of the Qin oncogene. Biochemical and biophysical research communications 9 11027514
2024 Discovery of the Natural Bibenzyl Compound Erianin in Dendrobium Inhibiting the Growth and EMT of Gastric Cancer through Downregulating the LKB1-SIK2/3-PARD3 Pathway. International journal of molecular sciences 8 39063214
2021 Exploring the stability of inhibitor binding to SIK2 using molecular dynamics simulation and binding free energy calculation. Physical chemistry chemical physics : PCCP 8 34086021
2023 Deficiency of salt-inducible kinase 2 (SIK2) promotes immune injury by inhibiting the maturation of lymphocytes. MedComm 7 37706195
2022 Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib. Computational and structural biotechnology journal 7 35685353
2022 Overexpression of circ PTK2 suppresses the progression of nonalcoholic fatty liver disease via the miR-200c/SIK2/PI3K/Akt axis. The Kaohsiung journal of medical sciences 6 35791807
2014 SIK2 regulates insulin secretion. Nature cell biology 6 24576898
2023 Inhibiting eukaryotic initiation factor 5A (eIF5A) hypusination attenuated activation of the SIK2 (salt-inducible kinase 2)-p4E-BP1 pathway involved in ovarian cancer cell proliferation and migration. Molecular biology reports 5 37219665
2018 Insulin induces Thr484 phosphorylation and stabilization of SIK2 in adipocytes. Cellular signalling 5 30586628
2021 SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA-deficient cells. Molecular oncology 4 34058059
2025 Activation of SIK2 inhibits gluconeogenesis and alleviates lipogenesis-induced inflammatory response by SIK2-CRTC2-ACC1 in hepatocytes of large yellow croaker (Larimichthys crocea). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 3 40067199
2025 PTH stimulation of Rankl transcription is regulated by SIK2 and 3 and mediated by CRTC2 and 3 through action of protein phosphatases 1, 2, 4, and 5. The Journal of biological chemistry 3 40609791
2025 SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome-lysosome fusion and rescues neurodegeneration in an Alzheimer's disease model. Translational neurodegeneration 3 41126299
2022 Designing of potent anti-diabetic molecules by targeting SIK2 using computational approaches. Molecular diversity 3 35727438
2016 SIK2 Promotes Ovarian Cancer Spread. Cancer discovery 3 27604487
2025 SIK2 inhibitor SIC-19 enhances the sensitivity of PARP inhibitors in triple-negative breast cancers and pancreatic cancers. Oncology research 2 40612876
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
2022 [Down-regulation of SIK2 expression alleviates myocardial ischemia-reperfusion injury in rats by inhibiting autophagy through the mTOR-ULK1 signaling pathway]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 35869774
2021 Relationship between salt-inducible kinase 2 (SIK2) and lymph node metastasis in colorectal cancer patients complicated with chronic schistosomiasis. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 2 34986532
2025 Computational insights into marine natural products as potential antidiabetic agents targeting the SIK2 protein kinase domain. SAR and QSAR in environmental research 1 39773122
2025 SIK2 Drives Pulmonary Fibrosis by Enhancing Fibroblast Glycolysis and Activation. Biomedicines 1 40868174
2024 SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo. Endocrinology 1 39158086
2024 SIK2 Controls the Homeostatic Character of the POMC Secretome Acutely in Response to Pharmacological ER Stress Induction. Cells 1 39329749
2026 Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes. JCI insight 0 41657312
2026 Exploring SIK2-CXCL5 interactions in neutrophils: A novel mechanism for modulating IL-23 and psoriasis progression. Immunology and cell biology 0 41867147
2026 A Review of SIK2 in Ovarian Cancer: Function and Emerging Targeted Therapies. OncoTargets and therapy 0 41908096
2026 The orally available SIK2/SIK3 inhibitor SK-124 increases bone mass in hypogonadal male mice. JBMR plus 0 41908158
2026 The Novel Compound SIC-19 Triggers CUL4B-Mediated Ubiquitination and Degradation of SIK2. Molecular and cellular biology 0 42213109
2025 RETRACTION: SIK2-Positive Tumor Epithelial Cells in Breast Cancer Maybe Potential Anti-Cancer Messengers: A Systematic Analysis from a Single-Cell Perspective. Environmental toxicology 0 40059847
2025 SIK2 activates the autophagy‒apoptosis pathway through SP1 regulation to inhibit the progression of hepatocellular carcinoma. Frontiers in pharmacology 0 41111507
2025 Synergistic interplay and dual-target therapeutics: unraveling the coordinated network of SIK2 and PARP-1 in cancer development. Bioorganic chemistry 0 41265209
2024 SIK2: A Novel Negative Feedback Regulator of FGF2 Signaling. Advanced biology 0 39267218
2023 SIK2-positive tumor epithelial cells in breast cancer maybe potential anti-cancer messengers: A systematic analysis from a single-cell perspective. Environmental toxicology 0 37772720

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