Affinage

CAMK4

Calcium/calmodulin-dependent protein kinase type IV · UniProt Q16566

Length
473 aa
Mass
51.9 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CAMK4 encodes CaMKIV, a calcium/calmodulin-activated serine/threonine kinase that functions as a nuclear effector of calcium signaling, principally by phosphorylating and activating the transcription factor CREB and the related factor CREM to drive activity-dependent gene programs (PMID:11572782, PMID:19605628, PMID:24667640). Activation flows through an upstream CaMKK module (CaMKK2/CaMKKβ phosphorylating Thr196/200), which can be scaffolded or tuned by partner proteins such as TIPRL and DJ-1, and selective nuclear delivery of CaMKIV is achieved through direct binding to the C-terminal region of importin-α, which imports the kinase independently of importin-β (PMID:15719015, PMID:31232473, PMID:39076120). In neurons this nuclear CaMKIV→CREB axis is required for activity-induced c-Fos and BDNF expression and underlies long-term forms of plasticity including late-LTP, cerebellar LTD, synaptic scaling, neuronal survival, and dendritic growth downstream of TRPC6-mediated calcium entry (PMID:11572782, PMID:10433267, PMID:19605628, PMID:28592691, PMID:18559891). Beyond the nervous system, CaMKIV drives CREM/CREB-dependent transcriptional programs that govern T cell fates—suppressing IL-2 and promoting Th17 differentiation and Tfh expansion via Bcl6—linking the kinase to autoimmunity (PMID:15841182, PMID:24667640, PMID:38287012). CaMKIV also acts on non-transcription-factor substrates: it phosphorylates protamine-2 during spermiogenesis (and its loss causes male infertility), DRP1-Ser616 to promote mitochondrial fission during sepsis, 14-3-3β to destabilize synaptopodin and remodel podocyte actin via Rac1/RhoA, Notch1-IC to protect it from Fbw7-dependent degradation during osteoclastogenesis, OGT to enhance O-GlcNAcylation, and synapsin to regulate synaptic vesicle trafficking (PMID:10932193, PMID:32932146, PMID:29985166, PMID:23103515, PMID:18029144, PMID:28698220). It additionally tunes the GSK-3β/FBXW7/mTOR axis to control autophagy and inflammatory output and is itself negatively regulated by caspase-3 and calpain-mediated proteolysis during cell death (PMID:25070845, PMID:11149901, PMID:12064479). A de novo splice variant removing the C-terminal regulatory domain renders CaMKIV constitutively active, demonstrating that the autoregulatory domain restrains kinase output in humans (PMID:30262571).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Established the first defined physiological substrate and in vivo requirement for CaMKIV, showing it phosphorylates protamine-2 and is essential for the chromatin protein exchange of spermiogenesis.

    Evidence Targeted Camk4 knockout mice with in vitro kinase assay and spermatid histology

    PMID:10932193

    Open questions at the time
    • Whether protamine-2 phosphorylation is direct in vivo not fully resolved
    • Other spermatid substrates not identified
  2. 2001 High

    Showed that nuclear CaMKIV→CREB signaling is selectively required for the late, transcription-dependent phase of plasticity and memory, distinguishing it from early plasticity.

    Evidence Forebrain-restricted dominant-negative CaMKIV transgenic mice with LTP and behavioral readouts

    PMID:11572782

    Open questions at the time
    • Specific target genes downstream of CREB in memory not enumerated here
    • Cell-type specificity within forebrain not resolved
  3. 2001 Medium

    Defined CaMKIV as a bidirectional regulator of neuronal survival and identified caspase-3 cleavage as a feedback brake during apoptosis.

    Evidence Dominant-active/negative CaMKIV in cerebellar granule neurons with caspase-3 assay

    PMID:11149901

    Open questions at the time
    • Cleavage site and consequence for kinase activity not fully mapped
    • Single-lab
  4. 2005 High

    Resolved how CaMKIV reaches the nucleus, showing direct importin-α binding mediates importin-β-independent nuclear import.

    Evidence Permeabilized-cell import assays, direct binding, and in vivo microinjection

    PMID:15719015

    Open questions at the time
    • Regulation of import by calcium/activation state not addressed
    • Nuclear export pathway not defined here
  5. 2005 Medium

    Extended CaMKIV signaling beyond neurons, linking it to CREM-mediated IL-2 suppression in T cells and to lupus pathophysiology.

    Evidence Dominant-inactive CaMKIV in normal T cells with IL-2 promoter and CREM binding assays

    PMID:15841182

    Open questions at the time
    • Direct CaMKIV-CREM phosphorylation not shown here
    • Single-lab dominant-negative approach
  6. 2009 High

    Demonstrated a CaMKK2→CaMKIV→CREB→BDNF cascade controlling cerebellar granule cell migration, with rescue establishing necessity of each kinase.

    Evidence CaMKK2 and CaMKIV null mice with reexpression rescue and migration/BDNF readouts

    PMID:19605628

    Open questions at the time
    • Direct kinase-substrate steps inferred from pathway epistasis
    • BDNF autocrine loop dynamics not fully resolved
  7. 2014 High

    Identified CaMK4 as a Th17-selective driver acting via CREM-α and AKT/mTOR, nominating it as an autoimmunity therapeutic target.

    Evidence CaMK4 knockout mice, pharmacologic inhibition, and human SLE T cell siRNA

    PMID:24667640

    Open questions at the time
    • Direct CaMK4 substrates in the AKT/mTOR arm not pinpointed
    • Mechanism of Th17-selective CaMK4 induction unknown
  8. 2014 Medium

    Mapped a CaMKIV→GSK-3β/FBXW7→mTOR axis preserving mTOR and enabling autophagy and inflammatory cytokine output in macrophages and kidney during sepsis.

    Evidence CaMKIV null mice in LPS/CLP models with mTOR ubiquitination and GSK-3β phosphorylation assays

    PMID:25070845

    Open questions at the time
    • Whether GSK-3β is a direct CaMKIV substrate not definitively shown
    • Single-lab
  9. 2016 High

    Showed CaMKIV directly phosphorylates and stabilizes a non-transcription-factor substrate, Notch1-IC, by blocking Fbw7-dependent degradation to promote osteoclastogenesis.

    Evidence Co-IP, in vitro kinase assay, phospho-deficient mutant, and osteoclast differentiation assays

    PMID:23103515

    Open questions at the time
    • Phosphorylation site stoichiometry in vivo not quantified
    • Reciprocal validation of interaction limited
  10. 2018 High

    Defined a cytoplasmic CaMK4 function in podocytes, phosphorylating 14-3-3β to release/destabilize synaptopodin and remodeling Rac1/RhoA-dependent actin and motility.

    Evidence Overexpression/inhibition in podocytes with biochemical phosphorylation and targeted in vivo inhibitor delivery

    PMID:29985166

    Open questions at the time
    • Direct 14-3-3β phosphosite not specified here
    • How CaMK4 partitions between nuclear and cytoplasmic functions unclear
  11. 2018 Medium

    Provided human genetic evidence that the C-terminal regulatory domain restrains CaMKIV, since its loss via a de novo splice variant yields constitutive activity.

    Evidence Trio exome sequencing, cDNA splicing analysis, and kinase activity in proband cells

    PMID:30262571

    Open questions at the time
    • Single subject; phenotype-genotype correlation limited
    • Downstream pathway consequences in patient tissue not characterized
  12. 2020 Medium

    Connected CaMKIV to mitochondrial dynamics, showing direct DRP1-Ser616 phosphorylation promoting fission and a role in sepsis-associated respiratory slowing and mitophagy.

    Evidence CaMK4 knockout in CLP sepsis with in vitro DRP1 phosphorylation and fission/fusion immunoblotting

    PMID:32932146

    Open questions at the time
    • Direct PINK1 kinase relationship stated without full reconstitution
    • Single-lab
  13. 2024 High

    Established CaMK4 as a controller of Tfh expansion and humoral immunity through CREM-α-driven Bcl6 transcription, validated in mouse and human cells.

    Evidence T cell-specific knockout, immunization/autoimmunity models, and human Tfh inhibition

    PMID:38287012

    Open questions at the time
    • Direct CaMK4-CREMα phosphorylation step not shown here
    • Bcl6 enhancer-level regulation not mapped
  14. 2025 High

    Showed a TRPC6→CaMK4→CREB axis that transcriptionally represses Acta2 to limit hepatic stellate cell activation and fibrosis, with direct promoter occupancy demonstrated.

    Evidence ChIP/luciferase for CREB-Acta2, TRPC6 manipulation, and constitutively active CREB rescue in fibrosis models

    PMID:39887689

    Open questions at the time
    • Mechanism by which CREB represses rather than activates Acta2 not detailed
    • CaMK4 phosphosite on CREB in this context not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CaMKIV's substrate selection and subcellular partitioning are governed across its many contexts—nuclear CREB/CREM transcription versus cytoplasmic substrates (DRP1, 14-3-3β, synapsin, Notch1-IC, OGT)—remains unresolved.
  • No unifying structural/regulatory model explains tissue-specific substrate choice
  • Quantitative in vivo phosphoproteome of CaMKIV not established
  • Determinants of nuclear vs cytoplasmic activity unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 4 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 2 R-HSA-9609507 Protein localization 1
Partners
CAMKK2CREB1CREMKPNA (IMPORTIN-ALPHA)NOTCH1OGTTIPRLYWHAB

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CaMKIV is required for activity-induced CREB phosphorylation and c-Fos expression in forebrain neurons; dominant-negative CaMKIV in postnatal forebrain blocks late LTP (L-LTP) but not early LTP, demonstrating a specific role for nuclear CaMKIV signaling in long-term memory consolidation/retention. Transgenic mice expressing dominant-negative CaMKIV restricted to postnatal forebrain; hippocampal LTP recordings; behavioral memory tests Cell High 11572782
2000 CaMKIV (Camk4) phosphorylates protamine-2 in vitro; Camk4 knockout male mice are infertile due to impaired spermiogenesis, with specific loss of protamine-2 and prolonged retention of transition protein-2 in elongating spermatids, indicating a role for CaMKIV in the sequential exchange of basic nuclear proteins on chromatin during spermiogenesis. Targeted gene knockout in mice; in vitro kinase assay (CaMKIV phosphorylation of protamine-2); histological analysis of spermatids Nature genetics High 10932193
2005 CaMKIV is required for SLE serum IgG (via anti-TCR/CD3 autoantibodies)-induced overexpression of CREM and its increased binding to the IL-2 promoter, thereby suppressing IL-2 production in T cells; dominant-inactive CaMKIV abolished this effect. Dominant-inactive CaMKIV expression in normal T cells; IL-2 promoter activity assay; CREM binding assay; nuclear localization of CaMKIV assessed by subcellular fractionation The Journal of clinical investigation Medium 15841182
2014 CaMK4 is required for Th17 cell differentiation; genetic or pharmacologic inhibition of CaMK4 reduces IL-17 production by decreasing activation of CREM-α and the AKT/mTOR pathway; CaMK4 levels increase selectively under Th17-inducing conditions but not Treg, Th1, or Th2 conditions. CaMK4 knockout mice; pharmacologic inhibition; naive T cell differentiation assays; IL17A/IL17F mRNA measurement; CaMK4 siRNA in human SLE T cells The Journal of clinical investigation High 24667640
2005 Acute in vivo expression of constitutively active CaMKIV or CREB enhances NMDA receptor-mediated synaptic responses and LTP, and generates electrophysiological and morphological features consistent with 'silent synapses' in rodent hippocampus. Viral-mediated gene transfer of constitutively active CaMKIV in vivo; electrophysiology; morphological analysis Neuron High 15748849
1999 CaMKIV activation is necessary for the late phase of cerebellar LTD; dominant-inhibitory CaMKIV constructs attenuated the late phase of LTD in cultured Purkinje neurons, while inhibition of PKA or MAPK/RSK cascades had no effect. Particle-mediated transfection of dominant-inhibitory CaMKIV in cultured Purkinje neurons; LTD measurement by electrophysiology Neuron Medium 10433267
2012 CaMKIV activates endothelial nitric oxide synthase (eNOS) in vitro; CaMK4 knockout mice display hypertension, cardiac hypertrophy, and vascular/kidney damage, establishing CaMKIV as a regulator of vascular tone through eNOS activation. CaMK4 knockout mouse cardiovascular phenotyping; in vitro kinase assay demonstrating CaMKIV-dependent eNOS activation Journal of the American Heart Association Medium 23130158
2018 CaMK4 modulates podocyte motility by altering expression of GTPases Rac1 and RhoA; CaMK4 phosphorylates scaffold protein 14-3-3β, releasing and destabilizing synaptopodin; CaMK4 suppresses nephrin, synaptopodin, and actin fiber expression in podocytes. CaMK4 overexpression/inhibition in podocytes; in vivo and in vitro assays of podocyte motility; phosphorylation of 14-3-3β shown by biochemical assay; targeted delivery of CaMK4 inhibitor to podocytes in lupus-prone mice The Journal of clinical investigation High 29985166
2015 CaMKK2 signals through CaMKIV to control liver cancer cell growth; CaMKK2 acts as a scaffold assembling CaMKIV with mTOR/S6K pathway components to stimulate protein synthesis; ectopic expression of wild-type but not kinase-inactive CaMKK2 rescues growth defects from CaMKK2 loss. RNAi ablation of CaMKK2; ectopic expression of wild-type vs. kinase-inactive CaMKK2; CaMKIV-dependent signaling assays; in vivo tumorigenicity assays Hepatology Medium 25847065
2009 CaMKK2 and CaMKIV are required for BDNF-dependent cerebellar granule cell migration; loss of either kinase reduces CREB phosphorylation, BDNF mRNA (exons I and IV), and BDNF protein; reexpression of CaMKK2 or CaMKIV in null granule cells restores pCREB and BDNF; exogenous BDNF rescues migration in vitro. CaMKK2 and CaMKIV null mice; in vitro and in vivo granule cell migration assays; reexpression rescue experiments; CREB phosphorylation and BDNF measurement The Journal of neuroscience High 19605628
2005 Importin-α transports CaMKIV into the nucleus independently of importin-β; CaMKIV directly interacts with the C-terminal region of importin-α; the CaMKIV/importin-α complex does not form a ternary complex with importin-β; microinjection of importin-α-ΔIBB enhances nuclear translocation of CaMKIV in vivo. Digitonin-permeabilized cell nuclear import assay; direct binding assay (importin-α C-terminus pulldown); cytoplasmic microinjection of importin-α-ΔIBB; fluorescence microscopy The EMBO journal High 15719015
2017 CaMKIV jointly regulates excitatory synaptic scaling and intrinsic excitability in neocortical pyramidal neurons through a cell-autonomous bidirectional mechanism; dominant-negative and constitutively active nuclear CaMKIV manipulations shift spontaneous firing rates, but inhibitory synaptic scaling is unaffected by these manipulations. Dominant-negative and constitutively active nuclear CaMKIV expression in individual neocortical neurons; electrophysiological measurement of excitatory quantal amplitude, intrinsic excitability, and inhibitory quantal amplitude The Journal of neuroscience High 28592691
2007 CaMKII and CaMKIV act additively and in parallel to promote neuronal survival in spiral ganglion neurons; CaMKIV requires CREB to promote survival (consistent with its exclusive nuclear localization), whereas CaMKII promotes survival via functional inactivation of Bad, independent of CREB. Expression of dominant-inhibitory CaMKIV and GFP-AIP (CaMKII inhibitor) in neonatal rat spiral ganglion neurons; constitutively active CaMKII and CREB constructs; survival assays Molecular and cellular neurosciences Medium 17651987
2001 CaMKIV promotes neuronal survival; a dominant-active CaMKIV mutant inhibits apoptosis in cerebellar granule neurons under low-K+ conditions, while dominant-negative CaMKIV induces apoptosis under high-K+ conditions; caspase-3 cleaves CaMKIV during apoptosis, providing a feedback mechanism. Overexpression of dominant-active and dominant-negative CaMKIV mutants by gene transfer in cerebellar neurons; caspase-3 activity assay; CREB phosphorylation measurement FASEB journal Medium 11149901
2007 CaMKIV specifically phosphorylates and activates OGT (O-GlcNAc transferase) both in vivo and in vitro under depolarization conditions; CaMKIV-dependent OGT activation is required for AP-1 activation and TIMP-1 gene expression in neuronal cells. In vivo and in vitro kinase assay (CaMKIV phosphorylation of OGT); CaMK inhibitor experiments; AP-1 reporter assay Cellular signalling Medium 18029144
2008 CaMKIV is necessary for BDNF-induced phosphorylation of CREB and for overcoming MAG-mediated inhibition of axonal growth; pharmacologic inhibition or dominant-negative CaMKIV blocks the neurotrophin effect; calcium flux from intracellular stores is required for this CaMKIV signaling. Pharmacologic CaMKIV inhibition; dominant-negative CaMKIV overexpression; neurite outgrowth assay on MAG substrate; CREB phosphorylation measurement Molecular and cellular neurosciences Medium 18381242
2012 CaMK4 promotes osteoclast differentiation by directly interacting with and phosphorylating the Notch1 intracellular domain (Notch1-IC), which decreases Fbw7-dependent proteasomal degradation and increases Notch1-IC stability; kinase activity of CaMKIV is essential for this effect. Co-IP (direct interaction between CaMKIV and Notch1-IC); in vitro kinase assay; phosphorylation-deficient Notch1-IC mutant; ubiquitin-proteasome assay; osteoclast differentiation assay Biochimica et biophysica acta High 23103515
2020 CaMKIV mediates an adaptive slowing of oxidative respiration during sepsis; CaMKIV directly phosphorylates DRP1 at Ser616 to promote mitochondrial fission, reduces expression of fusion proteins Mfn1/2 and OPA-1, and acts as a direct PINK1 kinase to enable mitophagy. CaMK4 knockout mice subjected to CLP sepsis; in vitro phosphorylation assay (DRP1 Ser616); mitochondrial respiration measurement; immunoblotting for fission/fusion proteins and PINK1/Parkin Cell calcium Medium 32932146
2014 CaMKIV, through inhibitory serine phosphorylation of GSK-3β and inhibition of FBXW7 recruitment, prevents ubiquitin-proteasomal degradation of mTOR, thereby preserving mTOR expression and augmenting autophagy in macrophages and kidney cells during LPS-induced inflammation. CaMKIV null mice; LPS-induced autophagy assays; GSK-3β phosphorylation measurement; mTOR ubiquitination assay; CaMKIV inhibitor experiments Journal of immunology Medium 25070845
2017 Soluble amyloid-β (sAβ1-42) causes increased phosphorylation of CaMKIV and its substrate synapsin, which markedly inhibits synaptic vesicle trafficking along axons between synapses; a CaMKK inhibitor or phosphodeficient synapsin mutant prevented these defects and restored activity-dependent synaptogenesis. Quantum dot single-particle tracking of synaptic vesicles; CaMKK inhibitor; phosphodeficient synapsin mutant; calcium imaging; transgenic AD mouse neurons Science signaling Medium 28698220
2012 CaMK4 regulates β-cell proliferation and apoptosis in a CREB-dependent manner; constitutively active CaMK4 stimulates β-cell proliferation and survival, while dominant-negative CaMK4 increases apoptosis; CaMK4 acts upstream of CREB to induce IRS-2 expression, and CREB is required for CaMK4's effects. Constitutively active and dominant-negative CaMK4 expression in MIN6 β-cells; IRS-2 knockdown; CREB dominant-negative rescue experiments; proliferation and apoptosis assays PloS one Medium 23049845
2006 CaMKIV is required for development of opioid analgesic tolerance but not acute morphine analgesia or physical dependence; CaMKIV knockout mice show less morphine-induced CREB phosphorylation and less G-protein uncoupling from the µ-opioid receptor after chronic morphine. CaMKIV knockout mice; chronic morphine tolerance assay; CREB phosphorylation measurement; G-protein coupling assay for µ-opioid receptor The European journal of neuroscience Medium 16630062
2020 Loss of CAMK4 leads to abnormal post-translational modifications and turnover of transferrin in mouse cerebellum and liver, associated with iron dyshomeostasis; CAMKK2-CAMK4 signaling regulates intracellular Ca2+ homeostasis during transferrin receptor-mediated endocytosis. CAMK4 knockout mice; CRISPR/Cas9 CAMKK2/CAMK4 deleted HEK293 cells; transferrin trafficking assays; calcium homeostasis measurements; post-translational modification analysis Cell communication and signaling Medium 32460794
2024 CaMK4 controls Tfh cell expansion and function by regulating Bcl6 transcription through CREMα; in the absence of CaMK4 in T cells, germinal center formation and humoral immunity are impaired; in human Tfh cells, CaMK4 inhibition reduces BCL6 expression and IL-21 secretion, impairing plasmablast formation. T cell-specific CaMK4 knockout mice; immunization and autoimmunity models; Bcl6 transcription assay; CaMK4 inhibition in human Tfh cells; plasmablast formation assay Nature communications High 38287012
2018 A de novo splice-site variant (c.981+1G>A) in CAMK4 causes selective loss of the carboxy-terminal regulatory domain of CaMKIV and results in constitutive CaMKIV activity; biochemical studies in proband-derived cells confirmed an activating effect of the variant. Trio whole-exome sequencing; cDNA analysis of aberrant splicing; biochemical kinase activity assay in proband-derived cells; in silico structural comparison with known constitutively active synthetic mutants Cold Spring Harbor molecular case studies Medium 30262571
2006 CaMKIV phosphorylation controls HDAC5 cytoplasmic localization in undifferentiated H9C2 cells; CaMKIV (and/or PKD) keeps HDAC5 cytoplasmic in undifferentiated cells, while PP2A promotes nuclear HDAC5 in differentiated cells where it interacts with YY1 to regulate transcription. Subcellular fractionation; CaMKIV and PKD inhibitor/expression studies; HDAC5 localization by immunofluorescence; Co-IP of HDAC5 with YY1 American journal of physiology. Cell physiology Medium 16822951
2014 CaMKIV activates survival proteins AKT, SIRT1, and FOXO3A in vitro, establishing CaMKIV as an activator of these pro-longevity signaling proteins. In vitro cell-based analysis of CaMKIV activation of AKT, SIRT1, and FOXO3A Rejuvenation research Low 21612516
2008 TRPC6-mediated Ca2+ influx activates CaMKIV and promotes dendritic growth in hippocampal neurons; dominant-negative CaMKIV or inhibition of Ca2+ influx blocks TRPC6-induced dendritic growth; TRPC6 transgenic mice show enhanced CaMKIV and CREB phosphorylation and increased dendritic growth. TRPC6 overexpression/shRNA knockdown; dominant-negative CaMKIV; CaMKIV phosphorylation assay; dendritic morphology quantification; TRPC6 transgenic mice Journal of cell science Medium 18559891
2019 DJ-1 directly interacts with CaMKKβ and through this interaction modulates CaMKIV phosphorylation (Thr196/200) and CREB1 (Ser133) phosphorylation; Dj-1 knockout mice show decreased CaMKIV and CREB1 phosphorylation in substantia nigra with reduced tyrosine hydroxylase expression. DJ-1/CaMKKβ direct interaction assay; Dj-1 knockout mouse biochemical analysis; CaMKIV and CREB1 phosphorylation measurement; TH expression assay; CREB1 knockdown epistasis Journal of cellular physiology Medium 31232473
2014 CaMKIV, through inhibitory phosphorylation of GSK-3β and preservation of mTOR expression, is required for autophagy and IL-6 production in macrophages during sepsis; this CaMKIV-mTOR-dependent autophagy is also cytoprotective in the kidney during endotoxemia. CaMKIV null mice; LPS endotoxemia model; CLP sepsis model; autophagy assays; GSK-3β and mTOR phosphorylation/expression measurement; IL-6 ELISA Journal of immunology Medium 25070845
2022 CaMK4 overexpression in ADPKD cells promotes mTOR signaling and cystic cell proliferation; CaMK4 knockdown reduces mTOR abundance and S6K phosphorylation; pharmacologic CaMK4 inhibition reduces mTOR signaling, inhibits proliferation, and reduces in vitro cyst formation independently of AMPK. CaMK4 knockdown in ADPKD cells; KN-93 pharmacologic inhibition; S6K/S6 phosphorylation assay; in vitro cyst formation assay; AMPK pathway analysis Journal of molecular cell biology Medium 36002021
2017 RNAi screening identified CaMK4 as a host regulator specifically required for Cryptococcus neoformans uptake; pharmacologic CaMK4 inhibition recapitulates uptake defects; CaMK4-deficient mice show increased survival after C. neoformans infection, correlated with decreased expression of pattern recognition receptors on phagocytes. siRNA screen of 868 kinase/phosphatase genes; high-throughput imaging phagocytosis assay; CaMK4 inhibitor (pharmacologic); CaMK4 knockout mice infection model Infection and immunity Medium 28970273
2025 TRPC6 suppresses hepatic stellate cell (HSC) activation through CaMK4-mediated CREB phosphorylation; CREB directly interacts with the Acta2 promoter to inhibit its transcription; expression of constitutively active CREB1Y134F in HSCs attenuates BDL-induced liver fibrosis in TRPC6 knockout mice. ChIP and dual-luciferase reporter assays (CREB binding to Acta2 promoter); TRPC6 knockout/overexpression; adenoviral constitutively active CREB1Y134F expression; mouse liver fibrosis models; CaMK4 phosphorylation assay British journal of pharmacology High 39887689
2001 Sustained Ca2+ entry (via voltage-sensitive Ca2+ channels or high NMDA) leads to calpain-mediated selective proteolysis of nuclear CaMKIV in cerebellar granule neurons; proteolysis is attenuated by nifedipine, APV, and CaM kinase inhibitors, and exacerbated by nuclear export inhibitor leptomycin B; despite CaMKIV down-regulation, CaMKIV/CREB signaling is preserved. Immunoblotting for CaMKIV in cerebellar neurons under different K+/NMDA conditions; calpain inhibitor assay; leptomycin B nuclear export inhibition; CREB phosphorylation assay Journal of neurochemistry Medium 12064479
2014 CaMKIV, through inhibitory GSK-3β serine phosphorylation and FBXW7 inhibition, prevents mTOR ubiquitin-proteasomal degradation, thereby enabling mTOR-dependent autophagy in macrophages and kidney in the context of sepsis; this CaMKIV-mTOR-dependent autophagy is required for IL-6 production. CaMKIV null mice; LPS/CLP sepsis models; mTOR ubiquitination and expression assays; IL-6 measurement; GSK-3β phosphorylation assay Journal of immunology Medium 25070845
2009 CaMKK/CaMKIV cascade activation is required for exendin-4-induced glucokinase (GK) gene transcription in pancreatic β-cells; CaMKIV Thr196 phosphorylation peaks at 15 min after exendin-4 treatment; constitutively active CaMKIV enhances GK promoter activity. Reporter gene assay; real-time PCR; Western blot for CaMKIV Thr196 phosphorylation; CaMKK inhibitor STO-609; constitutively active CaMKIV expression in INS-1 cells Diabetes, obesity & metabolism Medium 19486109
2011 PKA activates and phosphorylates RORα4 at Ser-99 in vitro; CaMK-IV-triggered increases in RORα4 transcriptional activity are blocked by PKA inhibitor H89, indicating CaMKIV acts through PKA to activate RORα4. In vitro kinase assay; Ser-99 to Ala mutation of RORα4; PKA inhibitor H89; RORα4 transcriptional activity reporter assay Biochemical and biophysical research communications Medium 21514275
2014 IB4-binding DRG neurons express a novel 3'-UTR-extended CaMK4 mRNA isoform that is preferentially expressed in these neurons and associates with axonal localization of CaMKIV protein; in IB4+ axons, 20% of CaMKIV co-localizes with the endocytic marker Rab7 in axons co-expressing CAMKK. FISH with riboprobes; RACE and RT-PCR cDNA sequencing; quantitative PCR of FACS-sorted DRG neurons; immunohistochemical co-localization with Rab7 and CAMKK The Journal of comparative neurology Medium 23817991
2022 CaMK4 promotes NLRP3 inflammasome activation in type II alveolar epithelial cells during LPS-induced acute lung injury; inhibition or silencing of CaMK4 reduces NLRP3 and caspase-1 activation and IL-1β production in AEC II cells. CaMK4 inhibitor KN-93 and CaMK4 siRNA in A549 cells and LPS-induced ALI mice; NLRP3/caspase-1/IL-1β measurement by Western blot and ELISA; immunofluorescence Frontiers in immunology Medium 35734175
2007 CaMKIV and calcineurin A both transactivate the PGC-1α promoter in rat skeletal muscle; however, only CaMKIV (not calcineurin A) transactivates the cytochrome c promoter, demonstrating differential downstream target specificity. Gene electrotransfer of CaMKIV and calcineurin A expression vectors into rat tibialis anterior muscle; PGC-1α and cytochrome c promoter-reporter assays Pflugers Archiv Medium 17273866
2024 TIPRL binds to CaMKK2 and causes sustained CaMKK2-CaMK4 pathway activation; CaMK4 phosphorylates CREB at Ser129 and Ser133 for maximum CREB activation; activated CREB drives transcription of TIPRL, forming a positive feedback loop; this TIPRL-CaMKK2-CaMK4-CREB axis maintains lung CSC stemness and survival. Co-IP (TIPRL-CaMKK2 interaction); phosphorylation assays (CREB Ser129/Ser133); CREB reporter assay; TIPRL depletion in vivo lung metastasis model; CaMK4 activation measurement Advanced science Medium 39076120

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 227 11572782
2005 Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. The Journal of clinical investigation 191 15841182
2000 Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nature genetics 189 10932193
2014 CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. The Journal of clinical investigation 183 24667640
2005 Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 180 15748849
2016 Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proceedings of the National Academy of Sciences of the United States of America 151 27298345
2008 TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. Journal of cell science 142 18559891
1999 A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB. Neuron 142 10433267
2012 CaMK4 Gene Deletion Induces Hypertension. Journal of the American Heart Association 141 23130158
2001 Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 119 11149901
2018 CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. The Journal of clinical investigation 98 29985166
2015 The camKK2/camKIV relay is an essential regulator of hepatic cancer. Hepatology (Baltimore, Md.) 97 25847065
2009 BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 19605628
2005 Importin alpha transports CaMKIV to the nucleus without utilizing importin beta. The EMBO journal 78 15719015
2017 All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 28592691
2007 CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neurons. Molecular and cellular neurosciences 67 17651987
2013 TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling. Journal of neurochemistry 62 23875811
2007 o-GlcNAc transferase is activated by CaMKIV-dependent phosphorylation under potassium chloride-induced depolarization in NG-108-15 cells. Cellular signalling 62 18029144
2014 Sigma 1 receptor activation regulates brain-derived neurotrophic factor through NR2A-CaMKIV-TORC1 pathway to rescue the impairment of learning and memory induced by brain ischaemia/reperfusion. Psychopharmacology 61 25420607
2011 Association study on long-living individuals from Southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. Rejuvenation research 59 21612516
2014 CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. Journal of immunology (Baltimore, Md. : 1950) 52 25070845
2012 The CaMK4/CREB/IRS-2 cascade stimulates proliferation and inhibits apoptosis of β-cells. PloS one 50 23049845
2015 Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice. Journal of immunology (Baltimore, Md. : 1950) 49 26561550
2008 BDNF activates CaMKIV and PKA in parallel to block MAG-mediated inhibition of neurite outgrowth. Molecular and cellular neurosciences 49 18381242
2017 Evidence of vanillin binding to CAMKIV explains the anti-cancer mechanism in human hepatic carcinoma and neuroblastoma cells. Molecular and cellular biochemistry 48 28744811
2014 Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice. Molecular neurobiology 48 25316382
2019 MiR-129-5p inhibits liver cancer growth by targeting calcium calmodulin-dependent protein kinase IV (CAMK4). Cell death & disease 43 31624237
2006 Shuttling of HDAC5 in H9C2 cells regulates YY1 function through CaMKIV/PKD and PP2A. American journal of physiology. Cell physiology 42 16822951
2020 CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 32862457
2017 Activation of CaMKIV by soluble amyloid-β1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis. Science signaling 36 28698220
2005 Contribution of CaMKIV to injury and fear-induced ultrasonic vocalizations in adult mice. Molecular pain 35 15813959
2021 Sevoflurane induces inflammation of microglia in hippocampus of neonatal rats by inhibiting Wnt/β-Catenin/CaMKIV pathway. Journal of pharmacological sciences 34 33941321
2020 Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury. Scientific reports 34 32332879
2007 ER81 and CaMKIV identify anatomically and phenotypically defined subsets of mouse olfactory bulb interneurons. The Journal of comparative neurology 34 17394138
2009 Arsenic down-regulates the expression of Camk4, an important gene related to cerebellar LTD in mice. Neurotoxicology and teratology 33 19410645
2019 Hesperidin-CAMKIV interaction and its impact on cell proliferation and apoptosis in the human hepatic carcinoma and neuroblastoma cells. Journal of cellular biochemistry 30 31021496
2005 Genetic alteration of anxiety and stress-like behavior in mice lacking CaMKIV. Molecular pain 30 16102169
2016 Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus. Experimental and therapeutic medicine 29 27446275
2009 Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic beta-cell line. Diabetes, obesity & metabolism 28 19486109
2022 CaMK4 Promotes Acute Lung Injury Through NLRP3 Inflammasome Activation in Type II Alveolar Epithelial Cell. Frontiers in immunology 27 35734175
2017 The role of CaMK4 in immune responses. Modern rheumatology 27 29252071
2007 Calcineurin A and CaMKIV transactivate PGC-1alpha promoter, but differentially regulate cytochrome c promoter in rat skeletal muscle. Pflugers Archiv : European journal of physiology 26 17273866
2000 Influence of aging and caloric restriction on activation of Ras/MAPK, calcineurin, and CaMK-IV activities in rat T cells. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 26 10654619
1999 Age-related decline in activation of calcium/calmodulin-dependent phosphatase calcineurin and kinase CaMK-IV in rat T cells. Mechanisms of ageing and development 26 10656183
2021 Atractylodis rhizoma water extract attenuates fructose-induced glomerular injury in rats through anti-oxidation to inhibit TRPC6/p-CaMK4 signaling. Phytomedicine : international journal of phytotherapy and phytopharmacology 23 34325092
2012 Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability. Biochimica et biophysica acta 23 23103515
2001 Expression of Ca(2+)/calmodulin-dependent protein kinase IV (caMKIV) messenger RNA during murine embryogenesis. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 23 11457732
2022 Nrf2 improves hippocampal synaptic plasticity, learning and memory through the circ-Vps41/miR-26a-5p/CaMKIV regulatory network. Experimental neurology 22 35143833
2013 Late maternal hypothyroidism alters the expression of Camk4 in neocortical subplate neurons: a comparison with Nurr1 labeling. Cerebral cortex (New York, N.Y. : 1991) 21 23680840
2009 Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway. Journal of cellular and molecular medicine 21 19874424
2006 Evidence for a role of CaMKIV in the development of opioid analgesic tolerance. The European journal of neuroscience 21 16630062
1990 Genetic mapping of the gene for Ca2+/calmodulin-dependent protein kinase IV (Camk-4) to mouse chromosome 18. Genomics 21 1981056
2020 CAMKK2-CAMK4 signaling regulates transferrin trafficking, turnover, and iron homeostasis. Cell communication and signaling : CCS 20 32460794
2020 CaMKIV regulates mitochondrial dynamics during sepsis. Cell calcium 20 32932146
2018 A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder. Cold Spring Harbor molecular case studies 20 30262571
2017 Insulin Resistance Disrupts the Interaction Between AKT and the NMDA Receptor and the Inactivation of the CaMKIV/CREB Pathway in Minimal Hepatic Encephalopathy. Toxicological sciences : an official journal of the Society of Toxicology 20 28505381
2010 CaMKIV over-expression boosts cortical 4-7 Hz oscillations during learning and 1-4 Hz delta oscillations during sleep. Molecular brain 20 20497541
2016 Inhibition of CaMKIV relieves streptozotocin-induced diabetic neuropathic pain through regulation of HMGB1. BMC anesthesiology 19 27216039
2009 Impaired memory of eyeblink conditioning in CaMKIV KO mice. Behavioral neuroscience 19 19331466
2020 Chrysophanol improves memory ability of d-galactose and Aβ25-35 treated rat correlating with inhibiting tau hyperphosphorylation and the CaM-CaMKIV signal pathway in hippocampus. 3 Biotech 18 32117672
2020 Nicotine Rescues Depressive-like Behaviors via α7-type Nicotinic Acetylcholine Receptor Activation in CaMKIV Null Mice. Molecular neurobiology 17 32815115
2019 MiR-125a-5p Alleviates Dysfunction and Inflammation of Pentylenetetrazol- induced Epilepsy Through Targeting Calmodulin-dependent Protein Kinase IV (CAMK4). Current neurovascular research 17 31490757
2018 Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 30113881
2020 CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice. The Journal of endocrinology 16 31770098
2011 NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway. Biochemical and biophysical research communications 16 21762679
2002 Trophic agents that prevent neuronal apoptosis activate calpain and down-regulate CaMKIV. Journal of neurochemistry 16 12064479
2021 LIFU Alleviates Neuropathic Pain by Improving the KCC2 Expression and Inhibiting the CaMKIV-KCC2 Pathway in the L4-L5 Section of the Spinal Cord. Neural plasticity 15 33953740
2018 Calcium/Calmodulin-Dependent Protein Kinase IV (CaMKIV) Mediates Acute Skeletal Muscle Inflammatory Response. Inflammation 15 28971270
2014 IB4-binding sensory neurons in the adult rat express a novel 3' UTR-extended isoform of CaMK4 that is associated with its localization to axons. The Journal of comparative neurology 15 23817991
2011 Protein kinase A activates and phosphorylates RORα4 in vitro and takes part in RORα activation by CaMK-IV. Biochemical and biophysical research communications 15 21514275
2012 Involvement of CaMKIV in neurogenic effect with chronic fluoxetine treatment. The international journal of neuropsychopharmacology 14 22695008
2012 Novel mutations in calcium/calmodulin-dependent protein kinase IV (CAMK4) gene in infertile men. International journal of andrology 14 22897820
2003 CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. International journal of molecular medicine 14 12525874
2024 CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses. Nature communications 13 38287012
2022 Magnesium promotes osteogenesis via increasing OPN expression and activating CaM/CaMKIV/CREB1 pathway. Journal of biomedical materials research. Part B, Applied biomaterials 13 35106922
2021 Complement activation and increased expression of Syk, mucin-1 and CaMK4 in kidneys of patients with COVID-19. Clinical immunology (Orlando, Fla.) 13 34252574
2020 CaMK4 promotes abortion-related Th17 cell imbalance by activating AKT/mTOR signaling pathway. American journal of reproductive immunology (New York, N.Y. : 1989) 13 32738170
2024 TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39076120
2019 DJ-1 regulates tyrosine hydroxylase expression through CaMKKβ/CaMKIV/CREB1 pathway in vitro and in vivo. Journal of cellular physiology 12 31232473
2010 Exendin-4 regulates GLUT2 expression via the CaMKK/CaMKIV pathway in a pancreatic β-cell line. Metabolism: clinical and experimental 12 20598720
2022 CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation. Journal of molecular cell biology 10 36002021
2021 Atractylodin inhibits fructose-induced human podocyte hypermotility via anti-oxidant to down-regulate TRPC6/p-CaMK4 signaling. European journal of pharmacology 10 34780752
2020 Comparative transcriptome analysis reveals a potential role for CaMK4 in γδT17 cells from systemic lupus erythematosus patients with lupus nephritis. International immunopharmacology 10 31978801
2020 Huang-Pu-Tong-Qiao Formula Ameliorates Tau Phosphorylation by Inhibiting the CaM-CaMKIV Pathway. Evidence-based complementary and alternative medicine : eCAM 9 34046075
2023 Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice. International immunopharmacology 8 37094544
2022 CaMKIV/CREB/BDNF signaling pathway expression in prefrontal cortex, amygdala, hippocampus and hypothalamus in streptozotocin-induced diabetic mice with anxious-like behavior. Experimental brain research 8 35984483
2001 CaMKIV/Gr is dispensable for spermatogenesis and CREM-regulated transcription in male germ cells. American journal of physiology. Endocrinology and metabolism 8 11595648
2025 TRPC6 suppresses liver fibrosis by inhibiting hepatic stellate cell activation via CaMK4-CREB pathway. British journal of pharmacology 7 39887689
2024 Convergence on CaMK4: A Key Modulator of Autism-Associated Signaling Pathways in Neurons. Biological psychiatry 7 39442785
2022 Combination of panax ginseng and ginkgo biloba extracts attenuate cerebral ischemia injury with modulation of NLRP3 inflammasome and CAMK4/CREB pathway. Frontiers in pharmacology 7 36091745
2018 [Protective effects of genistein on Aβ₂₅₋₃₅-induced PC12 cell injury via regulating CaM-CaMKIV signaling pathway]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 7 29600624
2021 CaMKIV Signaling Is Not Essential for the Maintenance of Intrinsic or Synaptic Properties in Mouse Visual Cortex. eNeuro 6 34001638
2021 Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV. Cell death discovery 6 34127648
2020 In vitro treatment of 3 T3-L1 adipocytes with recombinant Calcium/calmodulin-dependent Protein Kinase IV (CaMKIV) limits ER stress and improves insulin sensitivity through inhibition of autophagy via the mTOR/CREB signaling pathway. BMC endocrine disorders 6 32660483
2020 The Regulating Mechanism of Chrysophanol on Protein Level of CaM-CaMKIV to Protect PC12 Cells Against Aβ25-35-Induced Damage. Drug design, development and therapy 6 32764873
2012 Sisters Acts: Converging Signaling Between CaMKII and CaMKIV, Two Members of the Same Family. Translational medicine @ UniSa 6 23905065
2024 PVT1 regulates hippocampal neuron apoptosis and inflammation in epilepsy by miR-206-3p-dependent regulation of CAMK4. General physiology and biophysics 5 39140685
2023 Identification of CaMK4 as a sex-difference-related gene in knee osteoarthritis. Annals of translational medicine 5 37007557
2017 RNA Interference Screening Reveals Host CaMK4 as a Regulator of Cryptococcal Uptake and Pathogenesis. Infection and immunity 5 28970273
2016 CAMK4 gene variation is associated with hypertension in a Uygur population. Genetics and molecular research : GMR 5 26909912

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