{"gene":"CAMK2D","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2023,"finding":"CAMK2D serves as a molecular scaffold for the RNF8-MAD2 complex in the mitotic checkpoint: phospho-Thr287 on CAMK2D interacts with the FHA domain of RNF8, concentrating the RNF8-MAD2 complex, while RNF8 competes with p31comet for binding to closed-conformer MAD2 via its RING domain to sustain the spindle assembly checkpoint signal in glioma stem cells.","method":"RNF8 proximity proteomics, Co-IP, domain mutagenesis (FHA- and RING-dependent rescue), functional mitotic progression assays in glioma stem cells","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping with domain mutants plus functional mitotic assay, single lab but multiple orthogonal methods","pmids":["37468549"],"is_preprint":false},{"year":2026,"finding":"CAMK2D overactivation (not mis-splicing per se) is the central pathogenic mechanism in RBM20 cardiomyopathy: Rbm20/Camk2d double-knockout mice are protected from heart failure and sudden cardiac death; re-expression of individual CAMK2D splice variants in double-KO mice reintroduced cardiac dysfunction; RBM20 loss increases phosphorylation of CAMK2D targets; and ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function in RBM20-p.Arg636Gln knockin mice.","method":"Double-knockout mouse genetics, splice-variant re-expression, phosphoproteomic analysis of CAMK2D targets, pharmacological inhibition with hesperadin in knockin mice","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis (double KO rescue), re-expression of isoforms, phosphoproteomics, and pharmacological validation in vivo, multiple orthogonal methods in one study","pmids":["42082791"],"is_preprint":false},{"year":2026,"finding":"Alternative splicing of CAMK2D produces a nuclear splice variant (CAMK2D-B, exon 14-containing); hyperphosphorylation near its nuclear localization signal prevents nuclear targeting under adrenergic stress, restricting CAMK2D-B to the cytosol; cytoplasm-restricted CAMK2D-B uniquely remodels the cardiomyocyte phosphoproteome and blunts calcium transients in engineered heart tissues compared with nuclear-competent CAMK2D-B.","method":"Paired pre/post-LVAD RNA-seq, quantitative phosphoproteomics of human myocardium, subcellular fractionation, primary rat cardiomyocyte functional assays, human engineered heart tissue calcium transient measurements","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multi-omics with phosphoproteomics, subcellular fractionation, and functional validation in engineered tissues; single lab but multiple orthogonal methods","pmids":["41487088"],"is_preprint":false},{"year":2023,"finding":"BBLN (bublin coiled-coil protein) physically binds CAMK2D and activates it; BBLN overexpression promotes cardiac inflammation, fibrosis, and necroptosis through CAMK2D activation, and a BBLN mutant with impaired CAMK2D binding is functionally inert. Downregulation of CAMK2D by siRNA retarded BBLN-induced heart failure symptoms.","method":"BBLN overexpression mouse model, CAMK2D-binding mutant of BBLN, siRNA knockdown of CAMK2D, cardiac functional and histological readouts","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — binding-deficient mutant plus siRNA epistasis plus in vivo phenotypic rescue, multiple orthogonal methods in one study","pmids":["38666071"],"is_preprint":false},{"year":2024,"finding":"CAMK2D is recruited by the hsa_circ_0001546/14-3-3 complex to phosphorylate Tau at Ser324, altering 14-3-3-bound Tau phosphorylation status and forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex; this complex drives Tau aggregation, lipid peroxide accumulation, and LPO-dependent (GPX4-independent) ferroptosis, inhibiting epithelial ovarian cancer peritoneal metastasis.","method":"Co-IP/complex formation assay, phosphorylation site identification (Ser324), ferroptosis rescue with ferrostatin-1 and TRx0237 in vivo, functional metastasis assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — complex formation and site-specific phosphorylation shown, in vivo rescue supports pathway, but single lab and mechanistic phosphorylation evidence is from abstract-level description only","pmids":["38634567"],"is_preprint":false},{"year":2026,"finding":"CAMK2D isoform 15 (containing exon 7) directly interacts with AKT and promotes phosphorylation of AKT at Thr308, activating anti-apoptotic signaling and conferring gefitinib resistance in lung adenocarcinoma; SNRPA1 is identified as the upstream splicing regulator that controls isoform 15 expression.","method":"Co-IP (CAMK2D isoform 15–AKT interaction), AKT Thr308 phosphorylation assay, isoform knockdown/overexpression in vitro and xenograft models, multi-omics splicing analysis","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and phosphorylation site demonstrated, functional xenograft rescue, single lab","pmids":["42152470"],"is_preprint":false},{"year":2026,"finding":"CaMK2D hyperactivation (increased phosphorylation) promotes epithelial apoptosis, tight junction disruption, and inflammatory cascades in intestinal ischemia-reperfusion injury; rapamycin attenuates these effects by decreasing CAMK2D expression and phosphorylation; siRNA knockdown of CAMK2D similarly attenuates these pathological manifestations.","method":"siRNA knockdown, OGD/R cell model and murine I/R model, western blot for CAMK2D phosphorylation, ELISA for cytokines, histological analysis, molecular docking (rapamycin–CAMK2D)","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA epistasis plus pharmacological modulation in two model systems, single lab","pmids":["42145667"],"is_preprint":false},{"year":2024,"finding":"CAMK2D gain-of-function variants cause dilated cardiomyopathy and neurodevelopmental disorder (intellectual disability, delayed speech, behavioral problems), while loss-of-function variants cause only neurological symptoms, establishing isoform-level functional distinctions in humans. Functional testing of patient variants demonstrated GoF and LoF effects.","method":"Patient cohort variant functional characterization, mouse and human genetic evidence, gain-of-function and loss-of-function variant testing","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with functional variant testing, replicated across multiple individuals, but mechanistic detail limited to GoF/LoF classification","pmids":["38272033"],"is_preprint":false},{"year":2025,"finding":"CAMK2D overexpression in retinal pigment epithelium (RPE) attenuates NaIO3-induced retinal degeneration and reduces apoptosis, while CAMK2D knockdown aggravates degeneration; CAMK2D exerts this protective effect at least in part by upregulating complement factor I (CFI) expression.","method":"AAV-mediated overexpression and knockdown in mouse RPE in vivo; lentiviral manipulation of ARPE-19 cells; ERG, OCT, TUNEL, flow cytometry, western blot; CFI knockdown epistasis","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo and in vitro models with epistasis (CAMK2D overexpression rescues CFI knockdown), single lab","pmids":["39873650"],"is_preprint":false},{"year":2022,"finding":"Silencing CAMK2D in spermatogonia from varicocele rat testes promotes spermatogonial proliferation, associated with downregulation of CAMKII, FOXO1, and β-catenin, placing CAMK2D upstream of FOXO1 and β-catenin in a pathway that restrains spermatogonial proliferation.","method":"siRNA-mediated CAMK2D silencing in vitro (CCK-8 proliferation assay), qRT-PCR and western blot for CAMKII, FOXO1, and β-catenin","journal":"Evidence-based complementary and alternative medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, pathway placement inferred from expression changes without rescue experiments","pmids":["35911132"],"is_preprint":false},{"year":2023,"finding":"CAMK2D is highly expressed in BAP1-deficient malignant mesothelioma cells and tissues (70% of MMe tissues); CaMKII inhibitor KN-93 selectively suppresses proliferation of BAP1-deficient cells and reduces tumor growth in xenograft models, identifying CAMK2D kinase activity as a vulnerability in BAP1-loss contexts.","method":"BAP1-KO cell generation, cDNA microarray and qRT-PCR, KN-93 pharmacological inhibition in vitro and xenograft in vivo","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic model plus pharmacological inhibition in vitro and in vivo, single lab, mechanism of BAP1-CAMK2D relationship not fully defined","pmids":["37479714"],"is_preprint":false},{"year":2023,"finding":"GnRH promotes FSH synthesis and secretion in rat adenohypophysis via the lncRNA-m23b/miR-23b-3p/CAMK2D axis, where lncRNA-m23b acts as a competing endogenous RNA to relieve miR-23b-3p-mediated repression of CAMK2D expression.","method":"RNA-seq of rat adenohypophysis before/after GnRH treatment, ceRNA network construction, validated by qRT-PCR of CAMK2D and FSH output","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily transcriptomic with limited direct functional validation of CAMK2D's role in FSH output","pmids":["37107604"],"is_preprint":false}],"current_model":"CAMK2D (CaMKIIδ) is a calcium/calmodulin-dependent serine/threonine kinase that functions in multiple cellular contexts: in the heart it undergoes alternative splicing to produce nuclear (CAMK2D-B) and cytoplasmic isoforms whose subcellular localization—controlled by phosphorylation near the nuclear localization signal—determines their distinct phosphoproteomic effects and calcium-handling consequences; overactivation of CAMK2D is the central pathogenic driver in RBM20 cardiomyopathy and is promoted by the BBLN scaffold protein; in mitosis, phospho-Thr287-CAMK2D scaffolds the RNF8-MAD2 complex via the RNF8 FHA domain to sustain the spindle assembly checkpoint; a specific isoform 15 (exon 7-containing) directly binds and activates AKT at Thr308 to drive drug resistance; and pathogenic variants in humans cause gain-of-function dilated cardiomyopathy with neurodevelopmental disorder or loss-of-function neurological phenotypes alone."},"narrative":{"mechanistic_narrative":"CAMK2D (CaMKIIδ) is a calcium/calmodulin-dependent serine/threonine kinase whose subcellular targeting, splice-isoform identity, and activation state determine context-specific signaling outputs across cardiac, mitotic, and oncogenic settings [PMID:42082791, PMID:41487088, PMID:42152470]. In the heart, CAMK2D overactivation—rather than mis-splicing itself—is the central pathogenic driver of RBM20 cardiomyopathy, established by genetic epistasis in which Rbm20/Camk2d double-knockout mice are protected and re-expression of individual splice variants reintroduces dysfunction, with the ATP-competitive CaMKII inhibitor hesperadin rescuing function in vivo [PMID:42082791]. Cardiac CAMK2D activity is amplified by the scaffold protein BBLN, which physically binds and activates the kinase to promote inflammation, fibrosis, and necroptosis [PMID:38666071]. Alternative splicing produces a nuclear variant (CAMK2D-B); phosphorylation near its nuclear localization signal under adrenergic stress restricts it to the cytosol, where it remodels the cardiomyocyte phosphoproteome and blunts calcium transients distinctly from the nuclear-competent form [PMID:41487088]. Beyond the heart, phospho-Thr287 CAMK2D scaffolds the RNF8–MAD2 complex through the RNF8 FHA domain to sustain the spindle assembly checkpoint in glioma stem cells [PMID:37468549], and a specific exon-7-containing isoform (isoform 15) directly binds AKT and promotes its Thr308 phosphorylation to confer drug resistance [PMID:42152470]. In humans, gain-of-function CAMK2D variants cause dilated cardiomyopathy with neurodevelopmental disorder, whereas loss-of-function variants produce neurological phenotypes alone [PMID:38272033]. CAMK2D kinase activity additionally functions as a phosphorylation hub in injury and cancer contexts, phosphorylating Tau at Ser324 to drive ferroptosis [PMID:38634567] and acting downstream of stress signals in intestinal ischemia-reperfusion injury [PMID:42145667].","teleology":[{"year":2023,"claim":"Established a non-catalytic scaffolding role for activated CAMK2D outside the cardiac context, linking it to mitotic checkpoint control.","evidence":"RNF8 proximity proteomics, Co-IP, FHA/RING domain mutagenesis, and mitotic progression assays in glioma stem cells","pmids":["37468549"],"confidence":"High","gaps":["Whether this scaffolding function operates in non-glioma cell types is untested","The kinase substrate(s) of CAMK2D in this checkpoint context, if any, are not defined","Upstream signals driving Thr287 phosphorylation in this setting are unaddressed"]},{"year":2023,"claim":"Identified BBLN as a direct physical activator of CAMK2D that converts kinase activation into cardiac pathology, defining an upstream control point.","evidence":"BBLN overexpression mouse model, CAMK2D-binding-deficient BBLN mutant, and CAMK2D siRNA epistasis with cardiac readouts","pmids":["38666071"],"confidence":"High","gaps":["The structural basis of BBLN–CAMK2D binding is not resolved","Whether BBLN regulates CAMK2D in non-cardiac tissues is unknown"]},{"year":2024,"claim":"Resolved the genotype-phenotype logic of human CAMK2D variants, showing that gain- versus loss-of-function dictates cardiac plus neurodevelopmental versus neurological-only disease.","evidence":"Patient cohort variant functional characterization with gain- and loss-of-function testing in mouse and human genetic systems","pmids":["38272033"],"confidence":"Medium","gaps":["Mechanistic detail beyond GoF/LoF classification is limited","Isoform-specific contributions to each phenotype are not separated"]},{"year":2024,"claim":"Showed CAMK2D can be recruited into a defined RNA-protein complex to phosphorylate a specific substrate residue and trigger ferroptosis, expanding its substrate repertoire beyond canonical targets.","evidence":"Co-IP/complex formation, Ser324 site identification, and ferroptosis rescue in ovarian cancer metastasis models","pmids":["38634567"],"confidence":"Medium","gaps":["Phosphorylation site evidence is from abstract-level description","Not independently confirmed in other systems","How circRNA/14-3-3 directs CAMK2D specificity is not structurally defined"]},{"year":2026,"claim":"Demonstrated by genetic epistasis that CAMK2D overactivation, not RBM20 mis-splicing per se, is the actionable driver of RBM20 cardiomyopathy.","evidence":"Rbm20/Camk2d double-KO rescue, splice-variant re-expression, phosphoproteomics, and hesperadin pharmacology in knockin mice","pmids":["42082791"],"confidence":"High","gaps":["Which CAMK2D phosphosubstrates mediate the protective effect is not fully enumerated","Long-term efficacy and specificity of CaMKII inhibition in humans is untested"]},{"year":2026,"claim":"Defined how NLS-proximal phosphorylation reroutes the nuclear CAMK2D-B isoform to the cytosol, producing distinct phosphoproteomic and calcium-handling outcomes under adrenergic stress.","evidence":"Human myocardium RNA-seq/phosphoproteomics, subcellular fractionation, and engineered heart tissue calcium transient assays","pmids":["41487088"],"confidence":"High","gaps":["The kinase responsible for the NLS-proximal phosphorylation is not identified","How cytosolic versus nuclear localization maps onto specific disease outcomes is incomplete"]},{"year":2026,"claim":"Linked a specific exon-7-containing CAMK2D isoform to direct AKT activation and drug resistance, establishing isoform-selective oncogenic signaling.","evidence":"Co-IP, AKT Thr308 phosphorylation assay, isoform manipulation in vitro and xenografts, with SNRPA1 splicing regulation","pmids":["42152470"],"confidence":"Medium","gaps":["Whether AKT Thr308 phosphorylation is direct or kinase-dependent is not fully dissected","Single-lab finding without reciprocal validation"]},{"year":2026,"claim":"Extended CAMK2D hyperactivation as a driver of epithelial apoptosis and barrier disruption to intestinal ischemia-reperfusion injury, with pharmacological reversibility.","evidence":"siRNA knockdown, OGD/R and murine I/R models, phospho-westerns, and rapamycin modulation with docking","pmids":["42145667"],"confidence":"Medium","gaps":["Direct substrates in the intestinal context are not identified","Rapamycin–CAMK2D relationship rests partly on docking"]},{"year":2025,"claim":"Identified a protective, CFI-upregulating role for CAMK2D in retinal pigment epithelium against oxidative degeneration, contrasting its pathogenic roles elsewhere.","evidence":"AAV/lentiviral overexpression and knockdown in mouse RPE and ARPE-19 cells with CFI knockdown epistasis","pmids":["39873650"],"confidence":"Medium","gaps":["The mechanism linking CAMK2D activity to CFI transcription is undefined","Single-lab finding"]},{"year":2023,"claim":"Associated CAMK2D kinase activity with a targetable vulnerability in BAP1-deficient mesothelioma.","evidence":"BAP1-KO cells, expression profiling, and KN-93 inhibition in vitro and in xenografts","pmids":["37479714"],"confidence":"Medium","gaps":["The molecular link between BAP1 loss and CAMK2D dependence is not defined","KN-93 selectivity for CAMK2D over other CaMKII isoforms is a confound"]},{"year":null,"claim":"The full substrate map of CAMK2D across its cardiac, mitotic, and oncogenic contexts, and how splice-isoform identity and localization deterministically select those substrates, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified substrate-specificity model across tissues","Structural basis of isoform- and partner-directed targeting is missing","Upstream kinases controlling NLS-proximal and Thr287/Thr287-equivalent phosphorylation events not fully mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,4,5]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,6,8]}],"complexes":["RNF8-MAD2 complex","hsa_circ_0001546/14-3-3/CAMK2D/Tau complex"],"partners":["RNF8","MAD2","BBLN","AKT","TAU","YWHAZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13557","full_name":"Calcium/calmodulin-dependent protein kinase type II subunit delta","aliases":[],"length_aa":499,"mass_kda":56.4,"function":"Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program (PubMed:17179159). Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis (PubMed:16690701). May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (By similarity)","subcellular_location":"Cell membrane, sarcolemma; Sarcoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q13557/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAMK2D","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAMK2G","stoichiometry":10.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAMK2D","total_profiled":1310},"omim":[{"mim_id":"614986","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II INHIBITOR 1; CAMK2N1","url":"https://www.omim.org/entry/614986"},{"mim_id":"607708","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II-DELTA; CAMK2D","url":"https://www.omim.org/entry/607708"},{"mim_id":"602123","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II-GAMMA; CAMK2G","url":"https://www.omim.org/entry/602123"},{"mim_id":"600812","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 1; SRSF1","url":"https://www.omim.org/entry/600812"},{"mim_id":"114078","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II-ALPHA; CAMK2A","url":"https://www.omim.org/entry/114078"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium tip","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":123.6}],"url":"https://www.proteinatlas.org/search/CAMK2D"},"hgnc":{"alias_symbol":[],"prev_symbol":["CAMKD"]},"alphafold":{"accession":"Q13557","domains":[{"cath_id":"3.30.200.20","chopping":"8-90","consensus_level":"high","plddt":91.1559,"start":8,"end":90},{"cath_id":"1.10.510.10","chopping":"95-298","consensus_level":"high","plddt":95.397,"start":95,"end":298},{"cath_id":"3.10.450.50","chopping":"346-470","consensus_level":"high","plddt":86.7714,"start":346,"end":470}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13557","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13557-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13557-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAMK2D","jax_strain_url":"https://www.jax.org/strain/search?query=CAMK2D"},"sequence":{"accession":"Q13557","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13557.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13557/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13557"}},"corpus_meta":[{"pmid":"28383548","id":"PMC_28383548","title":"miR-146a facilitates osteoarthritis by regulating cartilage homeostasis via targeting Camk2d and Ppp3r2.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28383548","citation_count":87,"is_preprint":false},{"pmid":"33230455","id":"PMC_33230455","title":"circRNA CDR1as Promotes Pulmonary Artery Smooth Muscle Cell Calcification by Upregulating CAMK2D and CNN3 via Sponging miR-7-5p.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33230455","citation_count":49,"is_preprint":false},{"pmid":"38272033","id":"PMC_38272033","title":"Role of CAMK2D in neurodevelopment and associated conditions.","date":"2024","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38272033","citation_count":24,"is_preprint":false},{"pmid":"34131397","id":"PMC_34131397","title":"MicroRNA-135b/CAMK2D Axis Contribute to Malignant Progression of Gastric Cancer through EMT Process Remodeling.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34131397","citation_count":19,"is_preprint":false},{"pmid":"30127991","id":"PMC_30127991","title":"Overexpression of SMARCA2 or CAMK2D is associated with cisplatin resistance in human epithelial ovarian cancer.","date":"2018","source":"Oncology 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ulcerative colitis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38274809","citation_count":6,"is_preprint":false},{"pmid":"37479714","id":"PMC_37479714","title":"CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37479714","citation_count":4,"is_preprint":false},{"pmid":"37372357","id":"PMC_37372357","title":"CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37372357","citation_count":3,"is_preprint":false},{"pmid":"37107604","id":"PMC_37107604","title":"Sequencing of the Pituitary Transcriptome after GnRH Treatment Uncovers the Involvement of lncRNA-m23b/miR-23b-3p/CAMK2D in FSH Synthesis and Secretion.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37107604","citation_count":3,"is_preprint":false},{"pmid":"41487088","id":"PMC_41487088","title":"Myocardial Recovery With Mechanical Circulatory Support Is Linked to Alternative Splicing and Subcellular Localization of CAMK2D.","date":"2026","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/41487088","citation_count":2,"is_preprint":false},{"pmid":"35911132","id":"PMC_35911132","title":"Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35911132","citation_count":1,"is_preprint":false},{"pmid":"40766763","id":"PMC_40766763","title":"Ethyl acetate extract of Knoxia roxburghii (Rubiaceae) down-regulates ECHDC1, CAMK2D, DDB1, UBA6, BIRC6, and HK1 proteins and ameliorates the symptoms of diabetes mellitus.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40766763","citation_count":0,"is_preprint":false},{"pmid":"42145667","id":"PMC_42145667","title":"Bioinformatics-driven insights: rapamycin-mediated CaMK2D inhibition alleviates intestinal ischemia-reperfusion injury.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42145667","citation_count":0,"is_preprint":false},{"pmid":"42082791","id":"PMC_42082791","title":"CAMK2D causes heart failure in mice with RBM20 cardiomyopathy.","date":"2026","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/42082791","citation_count":0,"is_preprint":false},{"pmid":"42152470","id":"PMC_42152470","title":"CAMK2D isoform 15 facilitates gefitinib resistance via AKT phosphorylation in lung adenocarcinoma.","date":"2026","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42152470","citation_count":0,"is_preprint":false},{"pmid":"41183881","id":"PMC_41183881","title":"Intron polymorphism in Camk2d is associated with ventricular arrhythmias in normal adult Sprague-Dawley rats.","date":"2025","source":"Experimental animals","url":"https://pubmed.ncbi.nlm.nih.gov/41183881","citation_count":0,"is_preprint":false},{"pmid":"41240683","id":"PMC_41240683","title":"RAW 264.7-derived exosomal miR-494-3p regulates inflammation and osteogenic differentiation of human periodontal ligament stem cells through regulating CAMK2D.","date":"2025","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/41240683","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14861,"output_tokens":3426,"usd":0.047987,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11024,"output_tokens":3784,"usd":0.07486,"stage2_stop_reason":"end_turn"},"total_usd":0.122847,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"CAMK2D serves as a molecular scaffold for the RNF8-MAD2 complex in the mitotic checkpoint: phospho-Thr287 on CAMK2D interacts with the FHA domain of RNF8, concentrating the RNF8-MAD2 complex, while RNF8 competes with p31comet for binding to closed-conformer MAD2 via its RING domain to sustain the spindle assembly checkpoint signal in glioma stem cells.\",\n      \"method\": \"RNF8 proximity proteomics, Co-IP, domain mutagenesis (FHA- and RING-dependent rescue), functional mitotic progression assays in glioma stem cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping with domain mutants plus functional mitotic assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37468549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAMK2D overactivation (not mis-splicing per se) is the central pathogenic mechanism in RBM20 cardiomyopathy: Rbm20/Camk2d double-knockout mice are protected from heart failure and sudden cardiac death; re-expression of individual CAMK2D splice variants in double-KO mice reintroduced cardiac dysfunction; RBM20 loss increases phosphorylation of CAMK2D targets; and ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function in RBM20-p.Arg636Gln knockin mice.\",\n      \"method\": \"Double-knockout mouse genetics, splice-variant re-expression, phosphoproteomic analysis of CAMK2D targets, pharmacological inhibition with hesperadin in knockin mice\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis (double KO rescue), re-expression of isoforms, phosphoproteomics, and pharmacological validation in vivo, multiple orthogonal methods in one study\",\n      \"pmids\": [\"42082791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Alternative splicing of CAMK2D produces a nuclear splice variant (CAMK2D-B, exon 14-containing); hyperphosphorylation near its nuclear localization signal prevents nuclear targeting under adrenergic stress, restricting CAMK2D-B to the cytosol; cytoplasm-restricted CAMK2D-B uniquely remodels the cardiomyocyte phosphoproteome and blunts calcium transients in engineered heart tissues compared with nuclear-competent CAMK2D-B.\",\n      \"method\": \"Paired pre/post-LVAD RNA-seq, quantitative phosphoproteomics of human myocardium, subcellular fractionation, primary rat cardiomyocyte functional assays, human engineered heart tissue calcium transient measurements\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multi-omics with phosphoproteomics, subcellular fractionation, and functional validation in engineered tissues; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41487088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BBLN (bublin coiled-coil protein) physically binds CAMK2D and activates it; BBLN overexpression promotes cardiac inflammation, fibrosis, and necroptosis through CAMK2D activation, and a BBLN mutant with impaired CAMK2D binding is functionally inert. Downregulation of CAMK2D by siRNA retarded BBLN-induced heart failure symptoms.\",\n      \"method\": \"BBLN overexpression mouse model, CAMK2D-binding mutant of BBLN, siRNA knockdown of CAMK2D, cardiac functional and histological readouts\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding-deficient mutant plus siRNA epistasis plus in vivo phenotypic rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38666071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAMK2D is recruited by the hsa_circ_0001546/14-3-3 complex to phosphorylate Tau at Ser324, altering 14-3-3-bound Tau phosphorylation status and forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex; this complex drives Tau aggregation, lipid peroxide accumulation, and LPO-dependent (GPX4-independent) ferroptosis, inhibiting epithelial ovarian cancer peritoneal metastasis.\",\n      \"method\": \"Co-IP/complex formation assay, phosphorylation site identification (Ser324), ferroptosis rescue with ferrostatin-1 and TRx0237 in vivo, functional metastasis assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — complex formation and site-specific phosphorylation shown, in vivo rescue supports pathway, but single lab and mechanistic phosphorylation evidence is from abstract-level description only\",\n      \"pmids\": [\"38634567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAMK2D isoform 15 (containing exon 7) directly interacts with AKT and promotes phosphorylation of AKT at Thr308, activating anti-apoptotic signaling and conferring gefitinib resistance in lung adenocarcinoma; SNRPA1 is identified as the upstream splicing regulator that controls isoform 15 expression.\",\n      \"method\": \"Co-IP (CAMK2D isoform 15–AKT interaction), AKT Thr308 phosphorylation assay, isoform knockdown/overexpression in vitro and xenograft models, multi-omics splicing analysis\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and phosphorylation site demonstrated, functional xenograft rescue, single lab\",\n      \"pmids\": [\"42152470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CaMK2D hyperactivation (increased phosphorylation) promotes epithelial apoptosis, tight junction disruption, and inflammatory cascades in intestinal ischemia-reperfusion injury; rapamycin attenuates these effects by decreasing CAMK2D expression and phosphorylation; siRNA knockdown of CAMK2D similarly attenuates these pathological manifestations.\",\n      \"method\": \"siRNA knockdown, OGD/R cell model and murine I/R model, western blot for CAMK2D phosphorylation, ELISA for cytokines, histological analysis, molecular docking (rapamycin–CAMK2D)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA epistasis plus pharmacological modulation in two model systems, single lab\",\n      \"pmids\": [\"42145667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAMK2D gain-of-function variants cause dilated cardiomyopathy and neurodevelopmental disorder (intellectual disability, delayed speech, behavioral problems), while loss-of-function variants cause only neurological symptoms, establishing isoform-level functional distinctions in humans. Functional testing of patient variants demonstrated GoF and LoF effects.\",\n      \"method\": \"Patient cohort variant functional characterization, mouse and human genetic evidence, gain-of-function and loss-of-function variant testing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with functional variant testing, replicated across multiple individuals, but mechanistic detail limited to GoF/LoF classification\",\n      \"pmids\": [\"38272033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAMK2D overexpression in retinal pigment epithelium (RPE) attenuates NaIO3-induced retinal degeneration and reduces apoptosis, while CAMK2D knockdown aggravates degeneration; CAMK2D exerts this protective effect at least in part by upregulating complement factor I (CFI) expression.\",\n      \"method\": \"AAV-mediated overexpression and knockdown in mouse RPE in vivo; lentiviral manipulation of ARPE-19 cells; ERG, OCT, TUNEL, flow cytometry, western blot; CFI knockdown epistasis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo and in vitro models with epistasis (CAMK2D overexpression rescues CFI knockdown), single lab\",\n      \"pmids\": [\"39873650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing CAMK2D in spermatogonia from varicocele rat testes promotes spermatogonial proliferation, associated with downregulation of CAMKII, FOXO1, and β-catenin, placing CAMK2D upstream of FOXO1 and β-catenin in a pathway that restrains spermatogonial proliferation.\",\n      \"method\": \"siRNA-mediated CAMK2D silencing in vitro (CCK-8 proliferation assay), qRT-PCR and western blot for CAMKII, FOXO1, and β-catenin\",\n      \"journal\": \"Evidence-based complementary and alternative medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, pathway placement inferred from expression changes without rescue experiments\",\n      \"pmids\": [\"35911132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAMK2D is highly expressed in BAP1-deficient malignant mesothelioma cells and tissues (70% of MMe tissues); CaMKII inhibitor KN-93 selectively suppresses proliferation of BAP1-deficient cells and reduces tumor growth in xenograft models, identifying CAMK2D kinase activity as a vulnerability in BAP1-loss contexts.\",\n      \"method\": \"BAP1-KO cell generation, cDNA microarray and qRT-PCR, KN-93 pharmacological inhibition in vitro and xenograft in vivo\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic model plus pharmacological inhibition in vitro and in vivo, single lab, mechanism of BAP1-CAMK2D relationship not fully defined\",\n      \"pmids\": [\"37479714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GnRH promotes FSH synthesis and secretion in rat adenohypophysis via the lncRNA-m23b/miR-23b-3p/CAMK2D axis, where lncRNA-m23b acts as a competing endogenous RNA to relieve miR-23b-3p-mediated repression of CAMK2D expression.\",\n      \"method\": \"RNA-seq of rat adenohypophysis before/after GnRH treatment, ceRNA network construction, validated by qRT-PCR of CAMK2D and FSH output\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily transcriptomic with limited direct functional validation of CAMK2D's role in FSH output\",\n      \"pmids\": [\"37107604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAMK2D (CaMKIIδ) is a calcium/calmodulin-dependent serine/threonine kinase that functions in multiple cellular contexts: in the heart it undergoes alternative splicing to produce nuclear (CAMK2D-B) and cytoplasmic isoforms whose subcellular localization—controlled by phosphorylation near the nuclear localization signal—determines their distinct phosphoproteomic effects and calcium-handling consequences; overactivation of CAMK2D is the central pathogenic driver in RBM20 cardiomyopathy and is promoted by the BBLN scaffold protein; in mitosis, phospho-Thr287-CAMK2D scaffolds the RNF8-MAD2 complex via the RNF8 FHA domain to sustain the spindle assembly checkpoint; a specific isoform 15 (exon 7-containing) directly binds and activates AKT at Thr308 to drive drug resistance; and pathogenic variants in humans cause gain-of-function dilated cardiomyopathy with neurodevelopmental disorder or loss-of-function neurological phenotypes alone.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAMK2D (CaMKIIδ) is a calcium/calmodulin-dependent serine/threonine kinase whose subcellular targeting, splice-isoform identity, and activation state determine context-specific signaling outputs across cardiac, mitotic, and oncogenic settings [#1, #2, #5]. In the heart, CAMK2D overactivation—rather than mis-splicing itself—is the central pathogenic driver of RBM20 cardiomyopathy, established by genetic epistasis in which Rbm20/Camk2d double-knockout mice are protected and re-expression of individual splice variants reintroduces dysfunction, with the ATP-competitive CaMKII inhibitor hesperadin rescuing function in vivo [#1]. Cardiac CAMK2D activity is amplified by the scaffold protein BBLN, which physically binds and activates the kinase to promote inflammation, fibrosis, and necroptosis [#3]. Alternative splicing produces a nuclear variant (CAMK2D-B); phosphorylation near its nuclear localization signal under adrenergic stress restricts it to the cytosol, where it remodels the cardiomyocyte phosphoproteome and blunts calcium transients distinctly from the nuclear-competent form [#2]. Beyond the heart, phospho-Thr287 CAMK2D scaffolds the RNF8–MAD2 complex through the RNF8 FHA domain to sustain the spindle assembly checkpoint in glioma stem cells [#0], and a specific exon-7-containing isoform (isoform 15) directly binds AKT and promotes its Thr308 phosphorylation to confer drug resistance [#5]. In humans, gain-of-function CAMK2D variants cause dilated cardiomyopathy with neurodevelopmental disorder, whereas loss-of-function variants produce neurological phenotypes alone [#7]. CAMK2D kinase activity additionally functions as a phosphorylation hub in injury and cancer contexts, phosphorylating Tau at Ser324 to drive ferroptosis [#4] and acting downstream of stress signals in intestinal ischemia-reperfusion injury [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a non-catalytic scaffolding role for activated CAMK2D outside the cardiac context, linking it to mitotic checkpoint control.\",\n      \"evidence\": \"RNF8 proximity proteomics, Co-IP, FHA/RING domain mutagenesis, and mitotic progression assays in glioma stem cells\",\n      \"pmids\": [\"37468549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this scaffolding function operates in non-glioma cell types is untested\", \"The kinase substrate(s) of CAMK2D in this checkpoint context, if any, are not defined\", \"Upstream signals driving Thr287 phosphorylation in this setting are unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified BBLN as a direct physical activator of CAMK2D that converts kinase activation into cardiac pathology, defining an upstream control point.\",\n      \"evidence\": \"BBLN overexpression mouse model, CAMK2D-binding-deficient BBLN mutant, and CAMK2D siRNA epistasis with cardiac readouts\",\n      \"pmids\": [\"38666071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structural basis of BBLN–CAMK2D binding is not resolved\", \"Whether BBLN regulates CAMK2D in non-cardiac tissues is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the genotype-phenotype logic of human CAMK2D variants, showing that gain- versus loss-of-function dictates cardiac plus neurodevelopmental versus neurological-only disease.\",\n      \"evidence\": \"Patient cohort variant functional characterization with gain- and loss-of-function testing in mouse and human genetic systems\",\n      \"pmids\": [\"38272033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic detail beyond GoF/LoF classification is limited\", \"Isoform-specific contributions to each phenotype are not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed CAMK2D can be recruited into a defined RNA-protein complex to phosphorylate a specific substrate residue and trigger ferroptosis, expanding its substrate repertoire beyond canonical targets.\",\n      \"evidence\": \"Co-IP/complex formation, Ser324 site identification, and ferroptosis rescue in ovarian cancer metastasis models\",\n      \"pmids\": [\"38634567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site evidence is from abstract-level description\", \"Not independently confirmed in other systems\", \"How circRNA/14-3-3 directs CAMK2D specificity is not structurally defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated by genetic epistasis that CAMK2D overactivation, not RBM20 mis-splicing per se, is the actionable driver of RBM20 cardiomyopathy.\",\n      \"evidence\": \"Rbm20/Camk2d double-KO rescue, splice-variant re-expression, phosphoproteomics, and hesperadin pharmacology in knockin mice\",\n      \"pmids\": [\"42082791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which CAMK2D phosphosubstrates mediate the protective effect is not fully enumerated\", \"Long-term efficacy and specificity of CaMKII inhibition in humans is untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined how NLS-proximal phosphorylation reroutes the nuclear CAMK2D-B isoform to the cytosol, producing distinct phosphoproteomic and calcium-handling outcomes under adrenergic stress.\",\n      \"evidence\": \"Human myocardium RNA-seq/phosphoproteomics, subcellular fractionation, and engineered heart tissue calcium transient assays\",\n      \"pmids\": [\"41487088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase responsible for the NLS-proximal phosphorylation is not identified\", \"How cytosolic versus nuclear localization maps onto specific disease outcomes is incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked a specific exon-7-containing CAMK2D isoform to direct AKT activation and drug resistance, establishing isoform-selective oncogenic signaling.\",\n      \"evidence\": \"Co-IP, AKT Thr308 phosphorylation assay, isoform manipulation in vitro and xenografts, with SNRPA1 splicing regulation\",\n      \"pmids\": [\"42152470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AKT Thr308 phosphorylation is direct or kinase-dependent is not fully dissected\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended CAMK2D hyperactivation as a driver of epithelial apoptosis and barrier disruption to intestinal ischemia-reperfusion injury, with pharmacological reversibility.\",\n      \"evidence\": \"siRNA knockdown, OGD/R and murine I/R models, phospho-westerns, and rapamycin modulation with docking\",\n      \"pmids\": [\"42145667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates in the intestinal context are not identified\", \"Rapamycin–CAMK2D relationship rests partly on docking\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a protective, CFI-upregulating role for CAMK2D in retinal pigment epithelium against oxidative degeneration, contrasting its pathogenic roles elsewhere.\",\n      \"evidence\": \"AAV/lentiviral overexpression and knockdown in mouse RPE and ARPE-19 cells with CFI knockdown epistasis\",\n      \"pmids\": [\"39873650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mechanism linking CAMK2D activity to CFI transcription is undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Associated CAMK2D kinase activity with a targetable vulnerability in BAP1-deficient mesothelioma.\",\n      \"evidence\": \"BAP1-KO cells, expression profiling, and KN-93 inhibition in vitro and in xenografts\",\n      \"pmids\": [\"37479714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular link between BAP1 loss and CAMK2D dependence is not defined\", \"KN-93 selectivity for CAMK2D over other CaMKII isoforms is a confound\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full substrate map of CAMK2D across its cardiac, mitotic, and oncogenic contexts, and how splice-isoform identity and localization deterministically select those substrates, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified substrate-specificity model across tissues\", \"Structural basis of isoform- and partner-directed targeting is missing\", \"Upstream kinases controlling NLS-proximal and Thr287/Thr287-equivalent phosphorylation events not fully mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 4, 5]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 6, 8]}\n    ],\n    \"complexes\": [\"RNF8-MAD2 complex\", \"hsa_circ_0001546/14-3-3/CAMK2D/Tau complex\"],\n    \"partners\": [\"RNF8\", \"MAD2\", \"BBLN\", \"AKT\", \"Tau\", \"YWHAZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}