{"gene":"CAMK1D","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2000,"finding":"CKLiK (CAMK1D) is a novel Ca2+/calmodulin-dependent protein kinase expressed almost exclusively in human polymorphonuclear leukocytes (PMN); its kinase activity is dependent on Ca2+ and calmodulin as shown by in vitro phosphorylation of CREM; CaMK-kinase alpha enhances CKLiK activity; and inducible activation of CKLiK is sufficient to induce ERK MAP kinase activity and CREB transcriptional activity.","method":"In vitro kinase assay (phosphorylation of CREM), CaMKK-alpha co-activation assay, CRE-luciferase reporter assay, ionomycin stimulation of stably transfected cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with defined substrate, multiple orthogonal methods in a single study","pmids":["11050006"],"is_preprint":false},{"year":2005,"finding":"CKLiK (CAMK1D) is activated by fMLP and PAF stimulation (but not PMA) in human granulocytes in parallel with a rise in intracellular Ca2+; a cell-permeable peptide inhibitor of CKLiK blocks fMLP-induced ROS production, neutrophil migration on albumin-coated surfaces, and beta2-integrin-mediated adhesion, and reduces phagocytosis of Aspergillus fumigatus particles.","method":"Kinase activity assay in activated granulocytes, cell-permeable peptide inhibitor (CKLiK297-321), ROS assay, migration assay, adhesion assay, phagocytosis assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with peptide inhibitor across multiple defined cellular phenotypes, replicated in primary human cells","pmids":["15840691"],"is_preprint":false},{"year":2004,"finding":"Mouse CKLiK (mCamk1d/CAMK1D ortholog) is a PU.1 transcriptional target in murine erythroleukemia cells; two isoforms exist differing in the 3' coding region, one of which induces and the other inhibits apoptosis under low serum conditions, with only one isoform showing CREB-activating ability.","method":"Differential display, overexpression of individual isoforms in MEL cells, low-serum apoptosis assay, CRE-luciferase reporter assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with overexpression, but single lab and single model","pmids":["14980499"],"is_preprint":false},{"year":2008,"finding":"CAMK1D is amplified and overexpressed in basal-like breast cancer; engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells increases cell proliferation and induces epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion.","method":"Genomic copy number analysis, microarray expression, immunohistochemistry, engineered overexpression in MCF10A-type cells, proliferation assay, migration and invasion assay","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression with multiple defined phenotypic readouts, but no direct kinase mechanism established","pmids":["19383354"],"is_preprint":false},{"year":2013,"finding":"RNAi knockdown of CAMK1D in primary human hepatocytes alters the nuclear localization of CRTC2 (a mediator of gluconeogenesis and glycolysis regulation) in response to glucagon, implicating CAMK1D in hepatic glucose disposition.","method":"siRNA knockdown in primary human hepatocytes, CRTC2 nuclear localization assay, glycogen storage assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence following clean KD in human primary cells","pmids":["23840313"],"is_preprint":false},{"year":2014,"finding":"A type 2 diabetes GWAS SNP, rs11257655, at the CDC123/CAMK1D locus shows allele-specific transcriptional enhancer activity in insulinoma and hepatocellular carcinoma cells; the risk allele T shows greater activity than the non-risk allele C, and binds FOXA1 and FOXA2 in an allele-specific manner as demonstrated by EMSA, supershift, and allele-specific ChIP in human islets.","method":"Luciferase reporter assay, EMSA, supershift assay, allele-specific ChIP in human islets, open chromatin/histone modification analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including allele-specific ChIP in primary human tissue","pmids":["25211022"],"is_preprint":false},{"year":2017,"finding":"Transfer of miR-143-3p and miR-145-5p within extracellular vesicles from lung adenocarcinoma cells to endothelial cells reduces CAMK1D protein levels and increases tube formation, indicating that CAMK1D acts as an inhibitory kinase suppressing angiogenesis in endothelial cells.","method":"EV transfer assay, Western blot for CAMK1D protein, tube formation (angiogenesis) assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — functional readout with EV-mediated miRNA transfer, but indirect reduction of CAMK1D without direct kinase mechanistic follow-up","pmids":["29137392"],"is_preprint":false},{"year":2020,"finding":"CAMK1D is activated by CTL-mediated Fas-receptor stimulation in tumor cells; activated CAMK1D binds to and phosphorylates caspase-3, -6, and -7, thereby inhibiting their activation and function and conferring resistance to immune-mediated killing and anti-PD-L1 therapy.","method":"Genetic screen in PD-L1+ myeloma cells co-cultured with CTLs, Co-IP (CAMK1D binding to caspases), phosphorylation assay, Fas-receptor stimulation, pharmacological inhibition of CAMK1D, in vivo murine colorectal cancer model","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 1–2 — direct identification of caspases as substrates via binding and phosphorylation, validated in vivo","pmids":["32665263"],"is_preprint":false},{"year":2023,"finding":"CaMK1D is activated upon ghrelin stimulation in AgRP/NPY neurons; global and AgRP-neuron-specific Camk1d knockout mice are resistant to ghrelin-induced food intake, gain less body weight, and are protected from diet-induced obesity; lack of CaMK1D attenuates ghrelin-induced phosphorylation of CREB and CREB-dependent expression of AgRP/NPY neuropeptides in projections to the paraventricular nucleus.","method":"Global and conditional (AgRP/POMC neuron-specific) Camk1d knockout mice, ghrelin challenge, food intake assay, body weight measurement, high-fat diet model, CREB phosphorylation assay, neuropeptide expression analysis","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with multiple defined phenotypic and molecular readouts, replicated across models","pmids":["37277610"],"is_preprint":false},{"year":2024,"finding":"Podocyte-specific KLF6 triggers release of secretory ApoJ, which activates CaMK1D signaling in neighboring proximal tubule cells; CaMK1D is enriched in the first segment of the proximal tubule, and its activation attenuates mitochondrial fission and restores mitochondrial function under diabetic conditions.","method":"Conditional KLF6 overexpression in podocytes (murine DKD model), snRNA-seq, snATAC-seq, tandem mass spectrometry, mitochondrial fission assay, spatial localization by snRNA-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multi-omic orthogonal methods, in vivo conditional model, direct functional consequence on mitochondrial biology","pmids":["39271683"],"is_preprint":false},{"year":2021,"finding":"CaMK1D inhibitors prevent Aβ-induced tau hyperphosphorylation in mouse primary cortical neurons but do not protect cells from Aβ-induced toxicity, placing CAMK1D upstream of tau phosphorylation in neuronal Aβ signaling.","method":"Primary mouse cortical neuron culture, Aβ treatment, pharmacological CaMK1D inhibitors, tau phosphorylation assay, cell viability assay","journal":"Molecules","confidence":"Medium","confidence_rationale":"Tier 2 — direct pharmacological inhibition with defined molecular readout in primary neurons, single lab","pmids":["34946752"],"is_preprint":false},{"year":2025,"finding":"CAMK1D interacts with and phosphorylates AMPK at Thr172, which in turn activates PINK1 to modulate mitophagy, thereby supporting expansion of prostate cancer stem-like cells under enzalutamide treatment and driving enzalutamide resistance.","method":"Co-IP (CAMK1D–AMPK interaction), phosphorylation assay at AMPK Thr172, PINK1/Parkin mitophagy assay, siRNA knockdown, in vitro and in vivo (orthotopic) PCa models, nanoformulation-mediated CAMK1D targeting","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct substrate identification by Co-IP and phosphorylation assay with in vivo validation, single lab","pmids":["41419457"],"is_preprint":false},{"year":2026,"finding":"CAMK1D silencing (via EC@HNA nanoactivator) suppresses CREB phosphorylation at Ser133 in enzalutamide-resistant prostate cancer cells, transcriptionally repressing stemness regulators CD44, CD133, and NR4A1, and reducing regulatory T cell infiltration while enhancing CD8+ T cell cytotoxicity.","method":"siCAMK1D nanoactivator delivery, CREB Ser133 phosphorylation assay, stemness marker expression (CD44, CD133, NR4A1), immune cell profiling, xenograft and patient-derived organoid models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic follow-up with defined substrate (CREB Ser133) and multiple phenotypic readouts, validated in organoids and in vivo","pmids":["41510165"],"is_preprint":false}],"current_model":"CAMK1D is a Ca2+/calmodulin-dependent serine/threonine kinase activated downstream of Ca2+ signals (and upstream kinase CaMKK-alpha) that phosphorylates CREB to regulate transcription, phosphorylates AMPK at Thr172 to activate PINK1-dependent mitophagy, phosphorylates caspase-3/-6/-7 to block apoptosis in immune-resistant tumors, and acts in AgRP neurons to mediate ghrelin-induced CREB-dependent neuropeptide expression and food intake, while also regulating hepatic glucose homeostasis via CRTC2 nuclear localization and proximal tubule mitochondrial function via ApoJ-mediated signaling."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of CKLiK/CAMK1D as a novel Ca²⁺/calmodulin-dependent kinase established that a previously unknown member of the CaMK-I family is expressed preferentially in granulocytes, is activated by CaMKK-alpha, and can phosphorylate CREM and activate CREB-dependent transcription.","evidence":"In vitro kinase assay on CREM, CaMKK-alpha co-activation, CRE-luciferase reporter, ionomycin stimulation in stably transfected cells","pmids":["11050006"],"confidence":"High","gaps":["Endogenous substrates in granulocytes not identified","Upstream signals beyond calcium ionophore not characterized","Physiological role in innate immunity not yet tested"]},{"year":2004,"claim":"Discovery of two CAMK1D isoforms with opposing effects on apoptosis (one pro-apoptotic, one anti-apoptotic) revealed that alternative C-terminal regions confer distinct functional outputs, with only the CREB-activating isoform being anti-apoptotic.","evidence":"Overexpression of individual isoforms in murine erythroleukemia cells, low-serum apoptosis assay, CRE-luciferase reporter","pmids":["14980499"],"confidence":"Medium","gaps":["Isoform-specific substrates not identified","Single cell line model; not confirmed in primary hematopoietic cells","Mechanism linking CREB activation to survival not dissected"]},{"year":2005,"claim":"Demonstrating that peptide-mediated inhibition of CAMK1D blocks fMLP-induced ROS production, migration, adhesion, and phagocytosis in granulocytes established CAMK1D as a required effector of innate immune cell activation downstream of physiological chemoattractants.","evidence":"Cell-permeable inhibitor peptide (CKLiK297-321) in primary human granulocytes, ROS/migration/adhesion/phagocytosis assays","pmids":["15840691"],"confidence":"High","gaps":["Direct substrates mediating each granulocyte phenotype unknown","Genetic knockout confirmation not performed","Specificity of peptide inhibitor for CAMK1D over other CaMK-I family members not fully excluded"]},{"year":2008,"claim":"Finding CAMK1D amplification in basal-like breast cancer and showing that its overexpression drives proliferation and EMT extended the kinase's role from immune cells to oncogenic signaling, suggesting kinase activity can reprogram epithelial plasticity.","evidence":"Genomic copy number and expression analysis, engineered overexpression in MCF10A-type cells, proliferation/migration/invasion assays","pmids":["19383354"],"confidence":"Medium","gaps":["Direct kinase substrates mediating EMT not identified","Kinase-dead control not used","Not tested in loss-of-function in breast cancer cells"]},{"year":2013,"claim":"Showing that CAMK1D knockdown in primary hepatocytes alters CRTC2 nuclear localization in response to glucagon linked the kinase to hepatic glucose metabolism and provided a functional connection to the CDC123/CAMK1D type 2 diabetes GWAS locus.","evidence":"siRNA knockdown in primary human hepatocytes, CRTC2 nuclear localization and glycogen storage assays","pmids":["23840313"],"confidence":"Medium","gaps":["Whether CAMK1D directly phosphorylates CRTC2 or acts indirectly not determined","In vivo hepatic phenotype not examined","Relationship between GWAS SNP and CAMK1D expression level in hepatocytes not established"]},{"year":2014,"claim":"Demonstrating allele-specific enhancer activity at rs11257655 with differential FOXA1/FOXA2 binding in human islets provided a mechanistic basis for how the T2D GWAS variant at the CAMK1D locus may alter gene regulation in disease-relevant tissues.","evidence":"Luciferase reporter, EMSA, supershift, allele-specific ChIP in human islets, chromatin state analysis","pmids":["25211022"],"confidence":"High","gaps":["Whether the enhancer regulates CAMK1D versus CDC123 not definitively resolved","Effect of the variant on CAMK1D protein level or activity in islets not measured","Functional consequence for insulin secretion not tested"]},{"year":2020,"claim":"Identification of caspases-3, -6, and -7 as direct CAMK1D substrates whose phosphorylation blocks their activation revealed a mechanism by which tumor cells resist CTL-mediated and anti-PD-L1 immune killing, establishing CAMK1D as a druggable node in immune evasion.","evidence":"Genetic screen in PD-L1+ myeloma-CTL co-culture, Co-IP, phosphorylation assays, Fas-receptor stimulation, pharmacological inhibition, in vivo colorectal cancer model","pmids":["32665263"],"confidence":"High","gaps":["Specific phosphorylation sites on caspases not mapped","Whether CAMK1D-mediated caspase inhibition operates in non-tumor contexts unknown","Structural basis of CAMK1D-caspase interaction not resolved"]},{"year":2021,"claim":"Pharmacological inhibition of CAMK1D prevented Aβ-induced tau hyperphosphorylation in primary cortical neurons, positioning the kinase upstream of pathological tau modification without affecting Aβ-induced toxicity per se.","evidence":"Primary mouse cortical neurons, Aβ treatment, pharmacological CAMK1D inhibitors, tau phosphorylation and viability assays","pmids":["34946752"],"confidence":"Medium","gaps":["Whether CAMK1D directly phosphorylates tau or acts through intermediary kinases not determined","Inhibitor selectivity across CaMK family not fully characterized","In vivo relevance in neurodegeneration models not tested"]},{"year":2023,"claim":"Conditional knockout of Camk1d in AgRP neurons abolished ghrelin-induced food intake and protected from diet-induced obesity by attenuating CREB phosphorylation and AgRP/NPY neuropeptide expression, establishing CAMK1D as a required mediator of hypothalamic energy homeostasis.","evidence":"Global and AgRP-neuron-specific Camk1d KO mice, ghrelin challenge, food intake, body weight on high-fat diet, CREB phosphorylation and neuropeptide expression","pmids":["37277610"],"confidence":"High","gaps":["Whether CAMK1D directly phosphorylates CREB at Ser133 or acts through an intermediary in AgRP neurons not demonstrated in vitro","Contribution of CAMK1D in other neuron types to energy balance not explored","Downstream targets beyond AgRP/NPY not characterized"]},{"year":2024,"claim":"Multi-omic analysis of diabetic kidney disease revealed that podocyte-derived ApoJ activates CAMK1D signaling in proximal tubule cells to attenuate mitochondrial fission, identifying a paracrine axis through which CAMK1D preserves mitochondrial integrity under diabetic stress.","evidence":"Conditional KLF6 overexpression in podocytes (murine DKD model), snRNA-seq, snATAC-seq, mass spectrometry, mitochondrial fission assay","pmids":["39271683"],"confidence":"High","gaps":["Direct CAMK1D substrates mediating mitochondrial fission inhibition not identified","Whether CAMK1D acts on DRP1 or other fission machinery not tested","Mechanism of ApoJ-to-CAMK1D signal transduction not resolved"]},{"year":2025,"claim":"Identification of AMPK as a direct CAMK1D substrate (phosphorylated at Thr172) linked the kinase to PINK1-dependent mitophagy, explaining how CAMK1D supports prostate cancer stem-like cell expansion and enzalutamide resistance.","evidence":"Co-IP of CAMK1D-AMPK, Thr172 phosphorylation assay, PINK1/Parkin mitophagy assay, siRNA knockdown, orthotopic PCa models","pmids":["41419457"],"confidence":"Medium","gaps":["Whether CAMK1D is the dominant AMPK Thr172 kinase in non-cancer contexts not addressed","Single-lab finding; independent replication needed","Structural basis for CAMK1D selectivity toward AMPK versus known AMPK kinases (LKB1, CaMKK2) not examined"]},{"year":null,"claim":"The full substrate repertoire of CAMK1D remains undefined, and it is unresolved whether its diverse physiological roles—immune activation, energy homeostasis, apoptosis resistance, mitochondrial maintenance—are mediated primarily through CREB, AMPK, and caspases or additional substrates, and whether isoform-specific functions dictate tissue-specific outcomes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Comprehensive phosphoproteomics to identify the full CAMK1D substrate landscape has not been performed","No crystal structure of CAMK1D is available to explain substrate selectivity","Isoform-specific signaling outputs have not been resolved beyond the initial 2004 observation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,8,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[9,11]}],"complexes":[],"partners":["CREB1","CAMKK1","CASP3","CASP6","CASP7","PRKAA1","CRTC2","CLU"],"other_free_text":[]},"mechanistic_narrative":"CAMK1D is a Ca²⁺/calmodulin-dependent serine/threonine kinase that transduces calcium signals into diverse cellular responses including transcriptional regulation, innate immune cell activation, energy homeostasis, and apoptosis resistance. Upon calcium influx and activation by the upstream kinase CaMKK-alpha, CAMK1D phosphorylates CREB to drive CRE-dependent transcription—a mechanism operative in granulocyte activation, ghrelin-stimulated AgRP/NPY neuropeptide expression controlling food intake, and cancer cell stemness—and phosphorylates AMPK at Thr172 to activate PINK1-dependent mitophagy [PMID:11050006, PMID:37277610, PMID:41419457, PMID:41510165]. In neutrophils, CAMK1D is required for fMLP-induced ROS production, migration, adhesion, and phagocytosis [PMID:15840691], while in tumor cells Fas-receptor signaling activates CAMK1D to phosphorylate and inhibit caspases-3, -6, and -7, conferring resistance to immune-mediated killing [PMID:32665263]. CAMK1D also regulates hepatic glucose metabolism through control of CRTC2 nuclear localization, protects proximal tubule mitochondria from diabetic injury via ApoJ-mediated signaling, and contributes to Aβ-induced tau hyperphosphorylation in cortical neurons [PMID:23840313, PMID:39271683, PMID:34946752]."},"prefetch_data":{"uniprot":{"accession":"Q8IU85","full_name":"Calcium/calmodulin-dependent protein kinase type 1D","aliases":["CaM kinase I delta","CaM kinase ID","CaM-KI delta","CaMKI delta","CaMKID","CaMKI-like protein kinase","CKLiK"],"length_aa":385,"mass_kda":42.9,"function":"Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IU85/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAMK1D","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CAMK1D","total_profiled":1310},"omim":[{"mim_id":"613195","title":"WEILL-MARCHESANI SYNDROME 4; WMS4","url":"https://www.omim.org/entry/613195"},{"mim_id":"607957","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE I-DELTA; CAMK1D","url":"https://www.omim.org/entry/607957"},{"mim_id":"113705","title":"BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1","url":"https://www.omim.org/entry/113705"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":39.2},{"tissue":"retina","ntpm":53.6}],"url":"https://www.proteinatlas.org/search/CAMK1D"},"hgnc":{"alias_symbol":["CKLiK"],"prev_symbol":[]},"alphafold":{"accession":"Q8IU85","domains":[{"cath_id":"3.30.200.20","chopping":"14-100","consensus_level":"high","plddt":87.6872,"start":14,"end":100},{"cath_id":"1.10.510.10","chopping":"103-290","consensus_level":"high","plddt":88.1418,"start":103,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU85","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU85-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU85-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAMK1D","jax_strain_url":"https://www.jax.org/strain/search?query=CAMK1D"},"sequence":{"accession":"Q8IU85","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IU85.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IU85/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU85"}},"corpus_meta":[{"pmid":"18567820","id":"PMC_18567820","title":"Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18567820","citation_count":120,"is_preprint":false},{"pmid":"19833888","id":"PMC_19833888","title":"Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.","date":"2009","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/19833888","citation_count":106,"is_preprint":false},{"pmid":"25211022","id":"PMC_25211022","title":"Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25211022","citation_count":73,"is_preprint":false},{"pmid":"19383354","id":"PMC_19383354","title":"CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer.","date":"2008","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19383354","citation_count":52,"is_preprint":false},{"pmid":"29137392","id":"PMC_29137392","title":"Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29137392","citation_count":49,"is_preprint":false},{"pmid":"15840691","id":"PMC_15840691","title":"Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15840691","citation_count":42,"is_preprint":false},{"pmid":"11050006","id":"PMC_11050006","title":"Identification and characterization of CKLiK, a novel granulocyte Ca(++)/calmodulin-dependent kinase.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11050006","citation_count":31,"is_preprint":false},{"pmid":"32665263","id":"PMC_32665263","title":"CAMK1D Triggers Immune Resistance of Human Tumor Cells Refractory to Anti-PD-L1 Treatment.","date":"2020","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/32665263","citation_count":31,"is_preprint":false},{"pmid":"21909839","id":"PMC_21909839","title":"Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population.","date":"2011","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/21909839","citation_count":27,"is_preprint":false},{"pmid":"23840313","id":"PMC_23840313","title":"RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23840313","citation_count":21,"is_preprint":false},{"pmid":"37277610","id":"PMC_37277610","title":"CaMK1D signalling in AgRP neurons promotes ghrelin-mediated food intake.","date":"2023","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37277610","citation_count":18,"is_preprint":false},{"pmid":"35494053","id":"PMC_35494053","title":"CAMK1D Inhibits Glioma Through the PI3K/AKT/mTOR Signaling Pathway.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35494053","citation_count":17,"is_preprint":false},{"pmid":"28077997","id":"PMC_28077997","title":"Long non-coding RNA LOC283070 mediates the transition of LNCaP cells into androgen-independent cells possibly via CAMK1D.","date":"2016","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/28077997","citation_count":17,"is_preprint":false},{"pmid":"28079868","id":"PMC_28079868","title":"CDC123/CAMK1D gene rs12779790 polymorphism and rs10811661 polymorphism upstream of the CDKN2A/2B gene in women with gestational diabetes.","date":"2017","source":"Journal of perinatology : official journal of the California Perinatal Association","url":"https://pubmed.ncbi.nlm.nih.gov/28079868","citation_count":16,"is_preprint":false},{"pmid":"39271683","id":"PMC_39271683","title":"Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease.","date":"2024","source":"Nature 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population.","date":"2020","source":"Journal of diabetes and its complications","url":"https://pubmed.ncbi.nlm.nih.gov/33127268","citation_count":12,"is_preprint":false},{"pmid":"33660800","id":"PMC_33660800","title":"CircPRKCI regulates proliferation, migration and cycle of lung adenocarcinoma cells by targeting miR-219a-5p-regulated CAMK1D.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33660800","citation_count":9,"is_preprint":false},{"pmid":"33737811","id":"PMC_33737811","title":"LncRNA ILF3-AS1 Promotes the Progression of Colon Adenocarcinoma Cells Through the miR-619-5p/CAMK1D Axis.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33737811","citation_count":7,"is_preprint":false},{"pmid":"34946752","id":"PMC_34946752","title":"Effects of Specific Inhibitors for CaMK1D on a Primary Neuron Model for Alzheimer's Disease.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34946752","citation_count":6,"is_preprint":false},{"pmid":"40622640","id":"PMC_40622640","title":"Single-nucleus rna sequencing identifies universal camk1d upregulation and dysregulated c-ltmr subtypes as key drivers of paclitaxel-induced neuropathy.","date":"2025","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40622640","citation_count":2,"is_preprint":false},{"pmid":"41510165","id":"PMC_41510165","title":"Targeting CAMK1D-engineered nanoactivator suppresses cancer stem cell maintenance and immune evasion in enzalutamide-resistant prostate cancer.","date":"2026","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/41510165","citation_count":0,"is_preprint":false},{"pmid":"41419457","id":"PMC_41419457","title":"CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41419457","citation_count":0,"is_preprint":false},{"pmid":"41628662","id":"PMC_41628662","title":"CAMK1D and PI3 in low-density neutrophils are associated with the anti-hypertensive effects of valsartan.","date":"2026","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41628662","citation_count":0,"is_preprint":false},{"pmid":"41868793","id":"PMC_41868793","title":"CAMK1D as a potential therapeutic target for gut microbiota-driven promotion of lung adenocarcinoma development.","date":"2026","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/41868793","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.09.607388","title":"Lipidomic and Proteomic Insights from Extracellular Vesicles in Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes","date":"2024-08-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.09.607388","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16442,"output_tokens":3349,"usd":0.04978},"stage2":{"model":"claude-opus-4-6","input_tokens":6728,"output_tokens":3516,"usd":0.18231},"total_usd":0.23209,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CKLiK (CAMK1D) is a novel Ca2+/calmodulin-dependent protein kinase expressed almost exclusively in human polymorphonuclear leukocytes (PMN); its kinase activity is dependent on Ca2+ and calmodulin as shown by in vitro phosphorylation of CREM; CaMK-kinase alpha enhances CKLiK activity; and inducible activation of CKLiK is sufficient to induce ERK MAP kinase activity and CREB transcriptional activity.\",\n      \"method\": \"In vitro kinase assay (phosphorylation of CREM), CaMKK-alpha co-activation assay, CRE-luciferase reporter assay, ionomycin stimulation of stably transfected cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with defined substrate, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11050006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CKLiK (CAMK1D) is activated by fMLP and PAF stimulation (but not PMA) in human granulocytes in parallel with a rise in intracellular Ca2+; a cell-permeable peptide inhibitor of CKLiK blocks fMLP-induced ROS production, neutrophil migration on albumin-coated surfaces, and beta2-integrin-mediated adhesion, and reduces phagocytosis of Aspergillus fumigatus particles.\",\n      \"method\": \"Kinase activity assay in activated granulocytes, cell-permeable peptide inhibitor (CKLiK297-321), ROS assay, migration assay, adhesion assay, phagocytosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with peptide inhibitor across multiple defined cellular phenotypes, replicated in primary human cells\",\n      \"pmids\": [\"15840691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse CKLiK (mCamk1d/CAMK1D ortholog) is a PU.1 transcriptional target in murine erythroleukemia cells; two isoforms exist differing in the 3' coding region, one of which induces and the other inhibits apoptosis under low serum conditions, with only one isoform showing CREB-activating ability.\",\n      \"method\": \"Differential display, overexpression of individual isoforms in MEL cells, low-serum apoptosis assay, CRE-luciferase reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with overexpression, but single lab and single model\",\n      \"pmids\": [\"14980499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAMK1D is amplified and overexpressed in basal-like breast cancer; engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells increases cell proliferation and induces epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion.\",\n      \"method\": \"Genomic copy number analysis, microarray expression, immunohistochemistry, engineered overexpression in MCF10A-type cells, proliferation assay, migration and invasion assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with multiple defined phenotypic readouts, but no direct kinase mechanism established\",\n      \"pmids\": [\"19383354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNAi knockdown of CAMK1D in primary human hepatocytes alters the nuclear localization of CRTC2 (a mediator of gluconeogenesis and glycolysis regulation) in response to glucagon, implicating CAMK1D in hepatic glucose disposition.\",\n      \"method\": \"siRNA knockdown in primary human hepatocytes, CRTC2 nuclear localization assay, glycogen storage assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence following clean KD in human primary cells\",\n      \"pmids\": [\"23840313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A type 2 diabetes GWAS SNP, rs11257655, at the CDC123/CAMK1D locus shows allele-specific transcriptional enhancer activity in insulinoma and hepatocellular carcinoma cells; the risk allele T shows greater activity than the non-risk allele C, and binds FOXA1 and FOXA2 in an allele-specific manner as demonstrated by EMSA, supershift, and allele-specific ChIP in human islets.\",\n      \"method\": \"Luciferase reporter assay, EMSA, supershift assay, allele-specific ChIP in human islets, open chromatin/histone modification analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including allele-specific ChIP in primary human tissue\",\n      \"pmids\": [\"25211022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Transfer of miR-143-3p and miR-145-5p within extracellular vesicles from lung adenocarcinoma cells to endothelial cells reduces CAMK1D protein levels and increases tube formation, indicating that CAMK1D acts as an inhibitory kinase suppressing angiogenesis in endothelial cells.\",\n      \"method\": \"EV transfer assay, Western blot for CAMK1D protein, tube formation (angiogenesis) assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional readout with EV-mediated miRNA transfer, but indirect reduction of CAMK1D without direct kinase mechanistic follow-up\",\n      \"pmids\": [\"29137392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CAMK1D is activated by CTL-mediated Fas-receptor stimulation in tumor cells; activated CAMK1D binds to and phosphorylates caspase-3, -6, and -7, thereby inhibiting their activation and function and conferring resistance to immune-mediated killing and anti-PD-L1 therapy.\",\n      \"method\": \"Genetic screen in PD-L1+ myeloma cells co-cultured with CTLs, Co-IP (CAMK1D binding to caspases), phosphorylation assay, Fas-receptor stimulation, pharmacological inhibition of CAMK1D, in vivo murine colorectal cancer model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct identification of caspases as substrates via binding and phosphorylation, validated in vivo\",\n      \"pmids\": [\"32665263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CaMK1D is activated upon ghrelin stimulation in AgRP/NPY neurons; global and AgRP-neuron-specific Camk1d knockout mice are resistant to ghrelin-induced food intake, gain less body weight, and are protected from diet-induced obesity; lack of CaMK1D attenuates ghrelin-induced phosphorylation of CREB and CREB-dependent expression of AgRP/NPY neuropeptides in projections to the paraventricular nucleus.\",\n      \"method\": \"Global and conditional (AgRP/POMC neuron-specific) Camk1d knockout mice, ghrelin challenge, food intake assay, body weight measurement, high-fat diet model, CREB phosphorylation assay, neuropeptide expression analysis\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with multiple defined phenotypic and molecular readouts, replicated across models\",\n      \"pmids\": [\"37277610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Podocyte-specific KLF6 triggers release of secretory ApoJ, which activates CaMK1D signaling in neighboring proximal tubule cells; CaMK1D is enriched in the first segment of the proximal tubule, and its activation attenuates mitochondrial fission and restores mitochondrial function under diabetic conditions.\",\n      \"method\": \"Conditional KLF6 overexpression in podocytes (murine DKD model), snRNA-seq, snATAC-seq, tandem mass spectrometry, mitochondrial fission assay, spatial localization by snRNA-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic orthogonal methods, in vivo conditional model, direct functional consequence on mitochondrial biology\",\n      \"pmids\": [\"39271683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CaMK1D inhibitors prevent Aβ-induced tau hyperphosphorylation in mouse primary cortical neurons but do not protect cells from Aβ-induced toxicity, placing CAMK1D upstream of tau phosphorylation in neuronal Aβ signaling.\",\n      \"method\": \"Primary mouse cortical neuron culture, Aβ treatment, pharmacological CaMK1D inhibitors, tau phosphorylation assay, cell viability assay\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct pharmacological inhibition with defined molecular readout in primary neurons, single lab\",\n      \"pmids\": [\"34946752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAMK1D interacts with and phosphorylates AMPK at Thr172, which in turn activates PINK1 to modulate mitophagy, thereby supporting expansion of prostate cancer stem-like cells under enzalutamide treatment and driving enzalutamide resistance.\",\n      \"method\": \"Co-IP (CAMK1D–AMPK interaction), phosphorylation assay at AMPK Thr172, PINK1/Parkin mitophagy assay, siRNA knockdown, in vitro and in vivo (orthotopic) PCa models, nanoformulation-mediated CAMK1D targeting\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct substrate identification by Co-IP and phosphorylation assay with in vivo validation, single lab\",\n      \"pmids\": [\"41419457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAMK1D silencing (via EC@HNA nanoactivator) suppresses CREB phosphorylation at Ser133 in enzalutamide-resistant prostate cancer cells, transcriptionally repressing stemness regulators CD44, CD133, and NR4A1, and reducing regulatory T cell infiltration while enhancing CD8+ T cell cytotoxicity.\",\n      \"method\": \"siCAMK1D nanoactivator delivery, CREB Ser133 phosphorylation assay, stemness marker expression (CD44, CD133, NR4A1), immune cell profiling, xenograft and patient-derived organoid models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic follow-up with defined substrate (CREB Ser133) and multiple phenotypic readouts, validated in organoids and in vivo\",\n      \"pmids\": [\"41510165\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAMK1D is a Ca2+/calmodulin-dependent serine/threonine kinase activated downstream of Ca2+ signals (and upstream kinase CaMKK-alpha) that phosphorylates CREB to regulate transcription, phosphorylates AMPK at Thr172 to activate PINK1-dependent mitophagy, phosphorylates caspase-3/-6/-7 to block apoptosis in immune-resistant tumors, and acts in AgRP neurons to mediate ghrelin-induced CREB-dependent neuropeptide expression and food intake, while also regulating hepatic glucose homeostasis via CRTC2 nuclear localization and proximal tubule mitochondrial function via ApoJ-mediated signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CAMK1D is a Ca²⁺/calmodulin-dependent serine/threonine kinase that transduces calcium signals into diverse cellular responses including transcriptional regulation, innate immune cell activation, energy homeostasis, and apoptosis resistance. Upon calcium influx and activation by the upstream kinase CaMKK-alpha, CAMK1D phosphorylates CREB to drive CRE-dependent transcription—a mechanism operative in granulocyte activation, ghrelin-stimulated AgRP/NPY neuropeptide expression controlling food intake, and cancer cell stemness—and phosphorylates AMPK at Thr172 to activate PINK1-dependent mitophagy [PMID:11050006, PMID:37277610, PMID:41419457, PMID:41510165]. In neutrophils, CAMK1D is required for fMLP-induced ROS production, migration, adhesion, and phagocytosis [PMID:15840691], while in tumor cells Fas-receptor signaling activates CAMK1D to phosphorylate and inhibit caspases-3, -6, and -7, conferring resistance to immune-mediated killing [PMID:32665263]. CAMK1D also regulates hepatic glucose metabolism through control of CRTC2 nuclear localization, protects proximal tubule mitochondria from diabetic injury via ApoJ-mediated signaling, and contributes to Aβ-induced tau hyperphosphorylation in cortical neurons [PMID:23840313, PMID:39271683, PMID:34946752].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of CKLiK/CAMK1D as a novel Ca²⁺/calmodulin-dependent kinase established that a previously unknown member of the CaMK-I family is expressed preferentially in granulocytes, is activated by CaMKK-alpha, and can phosphorylate CREM and activate CREB-dependent transcription.\",\n      \"evidence\": \"In vitro kinase assay on CREM, CaMKK-alpha co-activation, CRE-luciferase reporter, ionomycin stimulation in stably transfected cells\",\n      \"pmids\": [\"11050006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous substrates in granulocytes not identified\",\n        \"Upstream signals beyond calcium ionophore not characterized\",\n        \"Physiological role in innate immunity not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery of two CAMK1D isoforms with opposing effects on apoptosis (one pro-apoptotic, one anti-apoptotic) revealed that alternative C-terminal regions confer distinct functional outputs, with only the CREB-activating isoform being anti-apoptotic.\",\n      \"evidence\": \"Overexpression of individual isoforms in murine erythroleukemia cells, low-serum apoptosis assay, CRE-luciferase reporter\",\n      \"pmids\": [\"14980499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Isoform-specific substrates not identified\",\n        \"Single cell line model; not confirmed in primary hematopoietic cells\",\n        \"Mechanism linking CREB activation to survival not dissected\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that peptide-mediated inhibition of CAMK1D blocks fMLP-induced ROS production, migration, adhesion, and phagocytosis in granulocytes established CAMK1D as a required effector of innate immune cell activation downstream of physiological chemoattractants.\",\n      \"evidence\": \"Cell-permeable inhibitor peptide (CKLiK297-321) in primary human granulocytes, ROS/migration/adhesion/phagocytosis assays\",\n      \"pmids\": [\"15840691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct substrates mediating each granulocyte phenotype unknown\",\n        \"Genetic knockout confirmation not performed\",\n        \"Specificity of peptide inhibitor for CAMK1D over other CaMK-I family members not fully excluded\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Finding CAMK1D amplification in basal-like breast cancer and showing that its overexpression drives proliferation and EMT extended the kinase's role from immune cells to oncogenic signaling, suggesting kinase activity can reprogram epithelial plasticity.\",\n      \"evidence\": \"Genomic copy number and expression analysis, engineered overexpression in MCF10A-type cells, proliferation/migration/invasion assays\",\n      \"pmids\": [\"19383354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct kinase substrates mediating EMT not identified\",\n        \"Kinase-dead control not used\",\n        \"Not tested in loss-of-function in breast cancer cells\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that CAMK1D knockdown in primary hepatocytes alters CRTC2 nuclear localization in response to glucagon linked the kinase to hepatic glucose metabolism and provided a functional connection to the CDC123/CAMK1D type 2 diabetes GWAS locus.\",\n      \"evidence\": \"siRNA knockdown in primary human hepatocytes, CRTC2 nuclear localization and glycogen storage assays\",\n      \"pmids\": [\"23840313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CAMK1D directly phosphorylates CRTC2 or acts indirectly not determined\",\n        \"In vivo hepatic phenotype not examined\",\n        \"Relationship between GWAS SNP and CAMK1D expression level in hepatocytes not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating allele-specific enhancer activity at rs11257655 with differential FOXA1/FOXA2 binding in human islets provided a mechanistic basis for how the T2D GWAS variant at the CAMK1D locus may alter gene regulation in disease-relevant tissues.\",\n      \"evidence\": \"Luciferase reporter, EMSA, supershift, allele-specific ChIP in human islets, chromatin state analysis\",\n      \"pmids\": [\"25211022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the enhancer regulates CAMK1D versus CDC123 not definitively resolved\",\n        \"Effect of the variant on CAMK1D protein level or activity in islets not measured\",\n        \"Functional consequence for insulin secretion not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of caspases-3, -6, and -7 as direct CAMK1D substrates whose phosphorylation blocks their activation revealed a mechanism by which tumor cells resist CTL-mediated and anti-PD-L1 immune killing, establishing CAMK1D as a druggable node in immune evasion.\",\n      \"evidence\": \"Genetic screen in PD-L1+ myeloma-CTL co-culture, Co-IP, phosphorylation assays, Fas-receptor stimulation, pharmacological inhibition, in vivo colorectal cancer model\",\n      \"pmids\": [\"32665263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific phosphorylation sites on caspases not mapped\",\n        \"Whether CAMK1D-mediated caspase inhibition operates in non-tumor contexts unknown\",\n        \"Structural basis of CAMK1D-caspase interaction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pharmacological inhibition of CAMK1D prevented Aβ-induced tau hyperphosphorylation in primary cortical neurons, positioning the kinase upstream of pathological tau modification without affecting Aβ-induced toxicity per se.\",\n      \"evidence\": \"Primary mouse cortical neurons, Aβ treatment, pharmacological CAMK1D inhibitors, tau phosphorylation and viability assays\",\n      \"pmids\": [\"34946752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CAMK1D directly phosphorylates tau or acts through intermediary kinases not determined\",\n        \"Inhibitor selectivity across CaMK family not fully characterized\",\n        \"In vivo relevance in neurodegeneration models not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional knockout of Camk1d in AgRP neurons abolished ghrelin-induced food intake and protected from diet-induced obesity by attenuating CREB phosphorylation and AgRP/NPY neuropeptide expression, establishing CAMK1D as a required mediator of hypothalamic energy homeostasis.\",\n      \"evidence\": \"Global and AgRP-neuron-specific Camk1d KO mice, ghrelin challenge, food intake, body weight on high-fat diet, CREB phosphorylation and neuropeptide expression\",\n      \"pmids\": [\"37277610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CAMK1D directly phosphorylates CREB at Ser133 or acts through an intermediary in AgRP neurons not demonstrated in vitro\",\n        \"Contribution of CAMK1D in other neuron types to energy balance not explored\",\n        \"Downstream targets beyond AgRP/NPY not characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multi-omic analysis of diabetic kidney disease revealed that podocyte-derived ApoJ activates CAMK1D signaling in proximal tubule cells to attenuate mitochondrial fission, identifying a paracrine axis through which CAMK1D preserves mitochondrial integrity under diabetic stress.\",\n      \"evidence\": \"Conditional KLF6 overexpression in podocytes (murine DKD model), snRNA-seq, snATAC-seq, mass spectrometry, mitochondrial fission assay\",\n      \"pmids\": [\"39271683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct CAMK1D substrates mediating mitochondrial fission inhibition not identified\",\n        \"Whether CAMK1D acts on DRP1 or other fission machinery not tested\",\n        \"Mechanism of ApoJ-to-CAMK1D signal transduction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of AMPK as a direct CAMK1D substrate (phosphorylated at Thr172) linked the kinase to PINK1-dependent mitophagy, explaining how CAMK1D supports prostate cancer stem-like cell expansion and enzalutamide resistance.\",\n      \"evidence\": \"Co-IP of CAMK1D-AMPK, Thr172 phosphorylation assay, PINK1/Parkin mitophagy assay, siRNA knockdown, orthotopic PCa models\",\n      \"pmids\": [\"41419457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CAMK1D is the dominant AMPK Thr172 kinase in non-cancer contexts not addressed\",\n        \"Single-lab finding; independent replication needed\",\n        \"Structural basis for CAMK1D selectivity toward AMPK versus known AMPK kinases (LKB1, CaMKK2) not examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full substrate repertoire of CAMK1D remains undefined, and it is unresolved whether its diverse physiological roles—immune activation, energy homeostasis, apoptosis resistance, mitochondrial maintenance—are mediated primarily through CREB, AMPK, and caspases or additional substrates, and whether isoform-specific functions dictate tissue-specific outcomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Comprehensive phosphoproteomics to identify the full CAMK1D substrate landscape has not been performed\",\n        \"No crystal structure of CAMK1D is available to explain substrate selectivity\",\n        \"Isoform-specific signaling outputs have not been resolved beyond the initial 2004 observation\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 8, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CREB1\",\n      \"CAMKK1\",\n      \"CASP3\",\n      \"CASP6\",\n      \"CASP7\",\n      \"PRKAA1\",\n      \"CRTC2\",\n      \"CLU\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}