{"gene":"PRKCQ","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"PRKCQ is a direct transcriptional target of RUNX1 in megakaryocytic cells. RUNX1 binds in vivo to the PRKCQ promoter region (-1225 to -1056 bp) containing a consensus RUNX1 site (ACCGCA at -1088 to -1069 bp), as shown by chromatin immunoprecipitation and EMSA. RUNX1 overexpression enhances PKCθ protein expression and promoter activity, while mutation of the RUNX1 site abolishes this enhancement; siRNA knockdown of RUNX1 decreases PRKCQ promoter activity and PKCθ protein levels.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), promoter-reporter assays with site-directed mutagenesis, siRNA knockdown, and overexpression in megakaryocytic cells","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (ChIP, EMSA, mutagenesis, promoter assay, siRNA KD) in a single focused study establishing the transcriptional regulatory mechanism","pmids":["21252065"],"is_preprint":false},{"year":2016,"finding":"PKCθ kinase activity promotes Rb phosphorylation and cell-cycle progression by stimulating ERK/MAPK activity. Overexpression of kinase-inactive PKCθ does not stimulate ERK/MAPK or Rb phosphorylation and does not promote growth-factor-independent proliferation, establishing that kinase activity is required for these downstream signaling events.","method":"Gain- and loss-of-function studies in MCF-10A cells using kinase-active vs. kinase-inactive PKCθ cDNA; immunoblot for p-Rb and p-ERK; small-molecule kinase inhibitor (AEB071); 3D culture growth assays","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/OE with defined molecular readouts (Rb phosphorylation, ERK activation) and pharmacological confirmation, single lab","pmids":["27663795"],"is_preprint":false},{"year":2016,"finding":"PRKCQ/PKCθ promotes anoikis resistance, anchorage-independent survival, and migration when expressed in non-transformed MCF-10A breast epithelial cells, and is required for growth and survival of a subset of triple-negative breast cancer cells in vitro and in vivo.","method":"shRNA knockdown and cDNA overexpression in MCF-10A and TNBC cell lines; anchorage-independent growth assays; anoikis assays; xenograft tumor models; PKCθ kinase inhibitor (AEB071) treatment","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with in vivo xenograft validation, single lab, multiple orthogonal phenotypic assays","pmids":["27663795"],"is_preprint":false},{"year":2020,"finding":"PRKCQ regulates chemotherapy sensitivity in TNBC cells by controlling the levels of pro-apoptotic Bim (a BCL2 family member). PRKCQ overexpression suppresses Bim and apoptosis triggered by paclitaxel or doxorubicin; PRKCQ downregulation or catalytically inactive PRKCQ fails to suppress Bim. Suppression of Bim prevents the enhanced apoptosis seen with combined PRKCQ knockdown and chemotherapy.","method":"shRNA knockdown and cDNA overexpression (wild-type vs. kinase-inactive) in MCF-10A and TNBC cell lines; immunoblot for Bim and BCL2-family members; apoptosis assays; small-molecule PRKCQ kinase inhibitor (17k); rescue experiments with Bim suppression","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement via rescue experiments (Bim suppression reverses phenotype), catalytic-dead mutant control, single lab","pmids":["32600444"],"is_preprint":false},{"year":2021,"finding":"Prkcq regulates proliferation, migration, and apoptosis of Schwann cells through the β-catenin, c-fos, and p-c-jun/c-jun pathways following sciatic nerve injury, and its expression decreases significantly during sciatic nerve repair.","method":"In vivo rat sciatic nerve injury model; in vitro Schwann cell gain- and loss-of-function (upregulation and downregulation of Prkcq); immunoblot and functional assays for proliferation, migration, and apoptosis; pathway analysis of β-catenin, c-fos, c-jun","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on expression-level readouts of downstream signaling molecules without direct mechanistic reconstitution","pmids":["34418453"],"is_preprint":false},{"year":2022,"finding":"PRKCQ-dependent activation of the NF-κB pathway mediates crocin-sensitive proliferation and inflammation in breast cancer cells. Reducing PRKCQ expression inhibits NF-κB activation (p-p65), and overexpression of PRKCQ reverses the anti-proliferative and anti-inflammatory effects of crocin.","method":"Western blot for PRKCQ and NF-κB p-p65/p65; siRNA/overexpression rescue experiments; CCK-8 and EdU proliferation assays; ELISA and RT-qPCR for TNF-α and IL-1β in breast cancer cell lines","journal":"Cytokine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by modulation + rescue, no direct biochemical reconstitution of PRKCQ→NF-κB link","pmids":["35447530"],"is_preprint":false},{"year":2025,"finding":"PRKCQ knockdown disrupts autophagic flux in oral squamous cell carcinoma cells by impairing lysosomal function and blocking autophagosome–lysosome fusion. Downstream, PRKCQ knockdown suppresses TRIM22 expression, and TRIM22 overexpression rescues lysosomal function and autophagosome–lysosome fusion, placing PRKCQ upstream of TRIM22 in autophagy regulation.","method":"shRNA knockdown of PRKCQ in OSCC cells; transcriptomic analysis; functional autophagic flux assays; lysosomal function assays; TRIM22 overexpression rescue; animal xenograft experiments; tissue microarray","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue (TRIM22 OE restoring phenotype after PRKCQ KD), transcriptomic + functional assays, single lab","pmids":["41764502"],"is_preprint":false},{"year":2025,"finding":"PRKCQ promotes Prkcq (ILC2-expressed) suppression of IL-4, IL-5, and IL-13 secretion and modulates tissue-resident macrophage (TRM) abundance in chronic pancreatitis. Prkcq knockdown in ILC2s reduced TRM numbers and alleviated pancreatic fibrosis in a mouse model, placing Prkcq upstream of ILC2 cytokine production and downstream TRM accumulation.","method":"Single-cell sequencing data analysis; mouse dibutyltin dichloride (DBTC) chronic pancreatitis model; siRNA-mediated Prkcq knockdown in ILC2s; histological assays (H&E, Masson, Sirius Red); cytokine expression analysis","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on knockdown with cytokine readouts, no direct biochemical mechanism established","pmids":["40706949"],"is_preprint":false},{"year":2026,"finding":"PRKCQ activation mediates anti-adipogenic effects in adipocytes; GLT (Ganoderma lucidum triterpenoids) upregulate PRKCQ expression and inhibit adipogenesis, and deletion of PRKCQ significantly reverses this anti-adipogenic effect, placing PRKCQ as a required mediator of adipogenesis suppression.","method":"High-fat diet mouse model; preadipocyte differentiation assays; PRKCQ knockout/deletion; expression analysis of adipogenic genes (PPARγ, C/EBPα, FASN, SCD-1); network pharmacology and machine learning target identification","journal":"Foods (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic deletion rescue experiment is suggestive but the mechanistic link between PRKCQ kinase activity and adipogenic transcription factors is not biochemically established; single lab","pmids":["41596924"],"is_preprint":false},{"year":2026,"finding":"CAP (cold atmospheric plasma) upregulates PRKCQ expression and activates NF-κB signaling to promote melanoblast-to-melanocyte differentiation; mechanistically, PRKCQ upregulation appears to be required upstream of NF-κB activation in this context.","method":"Murine vitiligo model (topical hydroquinone); CAP jet treatment; immortalized melanoblast cell line (iMC23); CCK-8 assays; flow cytometry; immunoblot for PRKCQ and NF-κB pathway components; melanogenic gene and melanin synthesis assays","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative pathway placement, no direct mutagenesis or reconstitution linking PRKCQ to NF-κB in this context","pmids":["42170107"],"is_preprint":false},{"year":1998,"finding":"The human PRKCQ gene locus was characterized: it spans ~62 kb on chromosome 10p15, is composed of 15 coding exons and 14 introns, and shares conserved intron positions and exon organization with the Drosophila melanogaster dPRKC gene.","method":"P1 genomic library cloning; FISH for chromosomal localization; long-range PCR and DNA sequencing to define all exon-intron boundaries","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization by sequencing and FISH, single study but definitive structural result","pmids":["9790596"],"is_preprint":false},{"year":2025,"finding":"PRKCQ is not required for spermatogenesis or male fertility in mice. Prkcq knockout males (generated by CRISPR/Cas9) show normal testicular histology, normal spermatogenic cell populations, normal sperm morphology, count, motility, and fertility despite high testicular PRKCQ expression.","method":"CRISPR/Cas9 Prkcq knockout mice; histological and immunofluorescence assays; computer-assisted sperm analysis; fertility testing; qPCR for other PKC family members","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean germline KO with comprehensive phenotypic analysis; well-controlled negative result","pmids":["40051302"],"is_preprint":false}],"current_model":"PRKCQ/PKCθ is a serine/threonine kinase whose expression in megakaryocytes is directly controlled at the transcriptional level by RUNX1; in T cells and a subset of triple-negative breast cancer cells its kinase activity drives ERK/MAPK-dependent Rb phosphorylation and cell-cycle progression, suppresses pro-apoptotic Bim to confer chemotherapy resistance, and promotes anoikis resistance and migration; in oral squamous cell carcinoma it sustains autophagic flux by maintaining TRIM22 expression and supporting autophagosome–lysosome fusion; in Schwann cells it modulates c-fos/c-jun pathways during nerve degeneration and regeneration; and it couples to NF-κB signaling in multiple contexts including breast cancer inflammation and melanoblast differentiation, while being dispensable for spermatogenesis in mice."},"narrative":{"mechanistic_narrative":"PRKCQ encodes PKCθ, a serine/threonine kinase whose expression and catalytic activity couple upstream regulatory inputs to proliferation, survival, and inflammatory signaling across diverse cell types [PMID:27663795]. In megakaryocytic cells, PRKCQ is a direct transcriptional target of RUNX1, which binds a consensus site in the PRKCQ promoter and drives PKCθ protein expression [PMID:21252065]. In breast epithelial and triple-negative breast cancer cells, PKCθ kinase activity stimulates ERK/MAPK signaling and Rb phosphorylation to promote cell-cycle progression and growth-factor-independent proliferation, while also conferring anoikis resistance, anchorage-independent survival, and migration [PMID:27663795]; the same catalytic activity suppresses pro-apoptotic Bim to limit chemotherapy-induced apoptosis, since Bim re-suppression reverses the sensitizing effect of PRKCQ loss [PMID:32600444]. In oral squamous cell carcinoma, PRKCQ sustains autophagic flux by maintaining TRIM22 expression and supporting lysosomal function and autophagosome–lysosome fusion, with TRIM22 overexpression rescuing the PRKCQ-knockdown phenotype [PMID:41764502]. Comprehensive germline knockout shows PRKCQ is dispensable for spermatogenesis and male fertility in mice despite high testicular expression [PMID:40051302]. The human gene spans ~62 kb on chromosome 10p15 across 15 coding exons [PMID:9790596]. The biochemical events directly linking PKCθ catalysis to ERK, NF-κB, and TRIM22 outputs have not been reconstituted in the available corpus.","teleology":[{"year":1998,"claim":"Established the genomic architecture of human PRKCQ, providing the structural foundation for studying its regulation and conservation.","evidence":"P1 genomic library cloning, FISH, and long-range PCR sequencing defining all exon-intron boundaries","pmids":["9790596"],"confidence":"Medium","gaps":["Does not address protein function or expression control","No isoform or promoter-element characterization"]},{"year":2011,"claim":"Answered how PRKCQ expression is controlled in megakaryocytes, identifying RUNX1 as a direct transcriptional driver of the gene.","evidence":"ChIP, EMSA, promoter-reporter mutagenesis, siRNA knockdown and overexpression in megakaryocytic cells","pmids":["21252065"],"confidence":"High","gaps":["Functional role of PKCθ in megakaryocytes not defined","Transcriptional control in other lineages unknown"]},{"year":2016,"claim":"Placed PKCθ kinase activity upstream of ERK/MAPK and Rb phosphorylation, showing catalytic activity is required for proliferation and oncogenic transformation phenotypes in breast cells.","evidence":"Kinase-active vs kinase-inactive cDNA, AEB071 inhibitor, immunoblot for p-Rb/p-ERK, anoikis and xenograft assays in MCF-10A and TNBC lines","pmids":["27663795"],"confidence":"Medium","gaps":["Direct kinase substrate linking PKCθ to ERK not identified","Mechanism of ERK activation not reconstituted"]},{"year":2020,"claim":"Defined a survival mechanism by which PKCθ catalytic activity suppresses pro-apoptotic Bim to confer chemotherapy resistance in TNBC.","evidence":"WT vs kinase-inactive overexpression, knockdown, apoptosis assays, and Bim-suppression rescue in MCF-10A and TNBC lines","pmids":["32600444"],"confidence":"Medium","gaps":["Biochemical step between PKCθ and Bim regulation unknown","Transcriptional vs post-translational control of Bim unresolved"]},{"year":2021,"claim":"Linked Prkcq to Schwann cell proliferation, migration, and apoptosis via β-catenin and c-fos/c-jun pathways during nerve injury.","evidence":"Rat sciatic nerve injury model with Schwann cell gain/loss-of-function and pathway immunoblotting","pmids":["34418453"],"confidence":"Low","gaps":["Pathway placement based on expression-level readouts without mechanistic reconstitution","Direct kinase targets not identified"]},{"year":2025,"claim":"Established PRKCQ as an upstream regulator of autophagic flux, acting through TRIM22 to maintain lysosomal function and autophagosome–lysosome fusion in OSCC.","evidence":"shRNA knockdown, transcriptomics, autophagic flux and lysosomal assays, TRIM22 overexpression rescue, and xenografts in OSCC cells","pmids":["41764502"],"confidence":"Medium","gaps":["Mechanism by which PRKCQ maintains TRIM22 expression unknown","Whether kinase activity is required not tested"]},{"year":2025,"claim":"Tested the requirement for PRKCQ in spermatogenesis, showing it is dispensable for male fertility despite high testicular expression.","evidence":"CRISPR/Cas9 germline knockout mice with histology, sperm analysis, and fertility testing","pmids":["40051302"],"confidence":"Medium","gaps":["Possible compensation by other PKC family members not excluded","Testicular function of PKCθ remains undefined"]},{"year":2025,"claim":"Implicated Prkcq in ILC2 cytokine production and tissue-resident macrophage accumulation during chronic pancreatitis.","evidence":"Single-cell sequencing, DBTC pancreatitis mouse model, and siRNA knockdown of Prkcq in ILC2s","pmids":["40706949"],"confidence":"Low","gaps":["No direct biochemical mechanism established","Pathway placement inferred from cytokine readouts"]},{"year":2026,"claim":"Identified PRKCQ as a required mediator of anti-adipogenic effects and as coupled to NF-κB during melanoblast differentiation.","evidence":"High-fat-diet adipogenesis model with PRKCQ deletion, and CAP-treated vitiligo/melanoblast model with NF-κB immunoblotting","pmids":["41596924","42170107"],"confidence":"Low","gaps":["Mechanistic link between PRKCQ kinase activity and adipogenic transcription factors not established","Correlative NF-κB placement without mutagenesis"]},{"year":null,"claim":"The direct catalytic substrates of PKCθ that connect it to ERK/MAPK, NF-κB, Bim, and TRIM22 outputs remain unidentified across all contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted phosphorylation substrate reported","No structural model of PKCθ in these signaling complexes","Kinase-activity requirement untested for autophagy and NF-κB phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04759","full_name":"Protein kinase C theta type","aliases":["nPKC-theta"],"length_aa":706,"mass_kda":81.9,"function":"Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation (PubMed:21964608). Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylates CCDC88A/GIV and inhibits its guanine nucleotide exchange factor activity (PubMed:23509302). Phosphorylates and activates LRRK1, which phosphorylates RAB proteins involved in intracellular trafficking (PubMed:36040231)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q04759/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKCQ","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":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRKCQ","total_profiled":1310},"omim":[{"mim_id":"612754","title":"GLUTAREDOXIN 3; GLRX3","url":"https://www.omim.org/entry/612754"},{"mim_id":"610859","title":"CAPPING PROTEIN REGULATOR AND MYOSIN 1 LINKER 2; CARMIL2","url":"https://www.omim.org/entry/610859"},{"mim_id":"609022","title":"RAPAMYCIN-INSENSITIVE COMPANION OF MTOR; RICTOR","url":"https://www.omim.org/entry/609022"},{"mim_id":"607210","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 11; CARD11","url":"https://www.omim.org/entry/607210"},{"mim_id":"606883","title":"INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4; IRAK4","url":"https://www.omim.org/entry/606883"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Centriolar satellite","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":30.8},{"tissue":"skeletal muscle","ntpm":115.2},{"tissue":"tongue","ntpm":104.8}],"url":"https://www.proteinatlas.org/search/PRKCQ"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q04759","domains":[{"cath_id":"2.60.40.150","chopping":"5-123","consensus_level":"high","plddt":80.9074,"start":5,"end":123},{"cath_id":"3.30.60.20","chopping":"155-286","consensus_level":"high","plddt":79.9101,"start":155,"end":286},{"cath_id":"3.30.200.20","chopping":"379-463_671-701","consensus_level":"high","plddt":87.9837,"start":379,"end":701},{"cath_id":"1.10.510.10","chopping":"468-645","consensus_level":"high","plddt":94.4887,"start":468,"end":645}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04759","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04759-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04759-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKCQ","jax_strain_url":"https://www.jax.org/strain/search?query=PRKCQ"},"sequence":{"accession":"Q04759","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04759.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04759/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04759"}},"corpus_meta":[{"pmid":"27663795","id":"PMC_27663795","title":"PRKCQ promotes oncogenic growth and anoikis resistance of a subset of triple-negative breast cancer cells.","date":"2016","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/27663795","citation_count":40,"is_preprint":false},{"pmid":"32619070","id":"PMC_32619070","title":"Long noncoding RNA PRKCQ-AS1 promotes CRC cell proliferation and migration via modulating miR-1287-5p/YBX1 axis.","date":"2020","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32619070","citation_count":29,"is_preprint":false},{"pmid":"32600444","id":"PMC_32600444","title":"PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim.","date":"2020","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/32600444","citation_count":28,"is_preprint":false},{"pmid":"35447530","id":"PMC_35447530","title":"Crocin attenuates NF-κB-mediated inflammation and proliferation in breast cancer cells by down-regulating PRKCQ.","date":"2022","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/35447530","citation_count":28,"is_preprint":false},{"pmid":"21252065","id":"PMC_21252065","title":"Platelet protein kinase C-theta deficiency with human RUNX1 mutation: PRKCQ is a transcriptional target of RUNX1.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21252065","citation_count":23,"is_preprint":false},{"pmid":"36732923","id":"PMC_36732923","title":"LncRNA PRKCQ-AS1 regulates paclitaxel resistance in triple-negative breast cancer cells through miR-361-5p/PIK3C3 mediated autophagy.","date":"2023","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36732923","citation_count":20,"is_preprint":false},{"pmid":"37358216","id":"PMC_37358216","title":"MiR-128-1-5p inhibits cell proliferation and induces cell apoptosis via targeting PRKCQ in colorectal cancer.","date":"2023","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37358216","citation_count":11,"is_preprint":false},{"pmid":"38092752","id":"PMC_38092752","title":"Fasting regulates mitochondrial function through lncRNA PRKCQ-AS1-mediated IGF2BPs in papillary thyroid carcinoma.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38092752","citation_count":11,"is_preprint":false},{"pmid":"26784953","id":"PMC_26784953","title":"Genetic Variation in the REL Gene Increases Risk of Behcet's Disease in a Chinese Han Population but That of PRKCQ Does Not.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26784953","citation_count":11,"is_preprint":false},{"pmid":"40103284","id":"PMC_40103284","title":"The Super Enhancer-Driven Long Noncoding RNA PRKCQ-AS1 Promotes Neuroblastoma Tumorigenesis by Interacting With MSI2 Protein and Is Targetable by Small Molecule Compounds.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40103284","citation_count":9,"is_preprint":false},{"pmid":"9790596","id":"PMC_9790596","title":"Molecular characterization of the human protein kinase C theta gene locus (PRKCQ).","date":"1998","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/9790596","citation_count":8,"is_preprint":false},{"pmid":"36643260","id":"PMC_36643260","title":"Role of immune-related lncRNAs--PRKCQ-AS1 and EGOT in the regulation of IL-1β, IL-6 and IL-8 expression in human gingival fibroblasts with TNF-α stimulation.","date":"2022","source":"Journal of dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36643260","citation_count":7,"is_preprint":false},{"pmid":"30828974","id":"PMC_30828974","title":"Missense mutation in PRKCQ is associated with Crohn's disease.","date":"2019","source":"Journal of digestive diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30828974","citation_count":6,"is_preprint":false},{"pmid":"27494091","id":"PMC_27494091","title":"CD3D and PRKCQ work together to discriminate between B-cell and T-cell acute lymphoblastic leukemia.","date":"2016","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27494091","citation_count":6,"is_preprint":false},{"pmid":"34418453","id":"PMC_34418453","title":"Protein kinase C theta (Prkcq) affects nerve degeneration and regeneration through the c-fos and c-jun pathways in injured rat sciatic nerves.","date":"2021","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34418453","citation_count":4,"is_preprint":false},{"pmid":"40433053","id":"PMC_40433053","title":"Identification of PRKCQ-AS1 as a Keratinocyte-Derived Exosomal lncRNA That Promotes Th17 Differentiation and IL-17 secretion in Psoriasis Through Bioinformatics, Machine Learning Algorithms, and Cell Experiments.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40433053","citation_count":3,"is_preprint":false},{"pmid":"38679027","id":"PMC_38679027","title":"DNA methyltransferases-associated long non-coding RNA PRKCQ-AS1 regulate DNA methylation in myelodysplastic syndrome.","date":"2024","source":"International journal of laboratory hematology","url":"https://pubmed.ncbi.nlm.nih.gov/38679027","citation_count":3,"is_preprint":false},{"pmid":"40597380","id":"PMC_40597380","title":"Clinical significance and biological function of PRKCQ-AS1/miR-582-3p expression in LUAD.","date":"2025","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/40597380","citation_count":3,"is_preprint":false},{"pmid":"41029829","id":"PMC_41029829","title":"Cancer-associated fibroblast promotes tamoxifen resistance in estrogen receptor positive breast cancer via exosomal LncRNA PRKCQ-AS1/miR-200a-3p/MKP1 axis-mediated apoptosis suppression.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41029829","citation_count":3,"is_preprint":false},{"pmid":"31908401","id":"PMC_31908401","title":"PRKCQ rs4750316 is associated with Vogt-Koyanagi-Harada syndrome in a Han Chinese population.","date":"2019","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/31908401","citation_count":3,"is_preprint":false},{"pmid":"40597019","id":"PMC_40597019","title":"Association of PRKCQ variants with breast cancer susceptibility and clinicopathological features.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40597019","citation_count":2,"is_preprint":false},{"pmid":"40051302","id":"PMC_40051302","title":"PRKCQ Is Dispensable for Spermatogenesis in Mice.","date":"2025","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/40051302","citation_count":0,"is_preprint":false},{"pmid":"40706949","id":"PMC_40706949","title":"Prkcq in ILC2 cells-enhanced the amounts of tissue-resident macrophages promotes pancreatic fibrosis in chronic pancreatitis.","date":"2025","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40706949","citation_count":0,"is_preprint":false},{"pmid":"41764502","id":"PMC_41764502","title":"PRKCQ-TRIM22 axis promotes proliferation and metastasis of oral squamous cell carcinoma via autophagosome‒lysosome pathway activation.","date":"2026","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41764502","citation_count":0,"is_preprint":false},{"pmid":"41596924","id":"PMC_41596924","title":"Ganoderma lucidum Triterpenoids Suppress Adipogenesis and Obesity via PRKCQ Activation: An Integrated In Vivo, In Vitro, and Systems Pharmacology Study.","date":"2026","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41596924","citation_count":0,"is_preprint":false},{"pmid":"42170107","id":"PMC_42170107","title":"Cold atmospheric plasma (CAP) stimulates melanoblast-to-melanocyte differentiation via PRKCQ upregulation and NF-κB activation.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42170107","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.12.25322158","title":"Analysis of rare coding variants in 470,000 UK Biobank participants reveals genetic associations with childhood asthma predisposition","date":"2025-02-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.12.25322158","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.13.24313664","title":"A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population","date":"2024-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.13.24313664","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17718,"output_tokens":3454,"usd":0.052482,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11178,"output_tokens":2916,"usd":0.064395,"stage2_stop_reason":"end_turn"},"total_usd":0.116877,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"PRKCQ is a direct transcriptional target of RUNX1 in megakaryocytic cells. RUNX1 binds in vivo to the PRKCQ promoter region (-1225 to -1056 bp) containing a consensus RUNX1 site (ACCGCA at -1088 to -1069 bp), as shown by chromatin immunoprecipitation and EMSA. RUNX1 overexpression enhances PKCθ protein expression and promoter activity, while mutation of the RUNX1 site abolishes this enhancement; siRNA knockdown of RUNX1 decreases PRKCQ promoter activity and PKCθ protein levels.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), promoter-reporter assays with site-directed mutagenesis, siRNA knockdown, and overexpression in megakaryocytic cells\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (ChIP, EMSA, mutagenesis, promoter assay, siRNA KD) in a single focused study establishing the transcriptional regulatory mechanism\",\n      \"pmids\": [\"21252065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKCθ kinase activity promotes Rb phosphorylation and cell-cycle progression by stimulating ERK/MAPK activity. Overexpression of kinase-inactive PKCθ does not stimulate ERK/MAPK or Rb phosphorylation and does not promote growth-factor-independent proliferation, establishing that kinase activity is required for these downstream signaling events.\",\n      \"method\": \"Gain- and loss-of-function studies in MCF-10A cells using kinase-active vs. kinase-inactive PKCθ cDNA; immunoblot for p-Rb and p-ERK; small-molecule kinase inhibitor (AEB071); 3D culture growth assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/OE with defined molecular readouts (Rb phosphorylation, ERK activation) and pharmacological confirmation, single lab\",\n      \"pmids\": [\"27663795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRKCQ/PKCθ promotes anoikis resistance, anchorage-independent survival, and migration when expressed in non-transformed MCF-10A breast epithelial cells, and is required for growth and survival of a subset of triple-negative breast cancer cells in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown and cDNA overexpression in MCF-10A and TNBC cell lines; anchorage-independent growth assays; anoikis assays; xenograft tumor models; PKCθ kinase inhibitor (AEB071) treatment\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with in vivo xenograft validation, single lab, multiple orthogonal phenotypic assays\",\n      \"pmids\": [\"27663795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRKCQ regulates chemotherapy sensitivity in TNBC cells by controlling the levels of pro-apoptotic Bim (a BCL2 family member). PRKCQ overexpression suppresses Bim and apoptosis triggered by paclitaxel or doxorubicin; PRKCQ downregulation or catalytically inactive PRKCQ fails to suppress Bim. Suppression of Bim prevents the enhanced apoptosis seen with combined PRKCQ knockdown and chemotherapy.\",\n      \"method\": \"shRNA knockdown and cDNA overexpression (wild-type vs. kinase-inactive) in MCF-10A and TNBC cell lines; immunoblot for Bim and BCL2-family members; apoptosis assays; small-molecule PRKCQ kinase inhibitor (17k); rescue experiments with Bim suppression\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement via rescue experiments (Bim suppression reverses phenotype), catalytic-dead mutant control, single lab\",\n      \"pmids\": [\"32600444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Prkcq regulates proliferation, migration, and apoptosis of Schwann cells through the β-catenin, c-fos, and p-c-jun/c-jun pathways following sciatic nerve injury, and its expression decreases significantly during sciatic nerve repair.\",\n      \"method\": \"In vivo rat sciatic nerve injury model; in vitro Schwann cell gain- and loss-of-function (upregulation and downregulation of Prkcq); immunoblot and functional assays for proliferation, migration, and apoptosis; pathway analysis of β-catenin, c-fos, c-jun\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on expression-level readouts of downstream signaling molecules without direct mechanistic reconstitution\",\n      \"pmids\": [\"34418453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRKCQ-dependent activation of the NF-κB pathway mediates crocin-sensitive proliferation and inflammation in breast cancer cells. Reducing PRKCQ expression inhibits NF-κB activation (p-p65), and overexpression of PRKCQ reverses the anti-proliferative and anti-inflammatory effects of crocin.\",\n      \"method\": \"Western blot for PRKCQ and NF-κB p-p65/p65; siRNA/overexpression rescue experiments; CCK-8 and EdU proliferation assays; ELISA and RT-qPCR for TNF-α and IL-1β in breast cancer cell lines\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by modulation + rescue, no direct biochemical reconstitution of PRKCQ→NF-κB link\",\n      \"pmids\": [\"35447530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCQ knockdown disrupts autophagic flux in oral squamous cell carcinoma cells by impairing lysosomal function and blocking autophagosome–lysosome fusion. Downstream, PRKCQ knockdown suppresses TRIM22 expression, and TRIM22 overexpression rescues lysosomal function and autophagosome–lysosome fusion, placing PRKCQ upstream of TRIM22 in autophagy regulation.\",\n      \"method\": \"shRNA knockdown of PRKCQ in OSCC cells; transcriptomic analysis; functional autophagic flux assays; lysosomal function assays; TRIM22 overexpression rescue; animal xenograft experiments; tissue microarray\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue (TRIM22 OE restoring phenotype after PRKCQ KD), transcriptomic + functional assays, single lab\",\n      \"pmids\": [\"41764502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCQ promotes Prkcq (ILC2-expressed) suppression of IL-4, IL-5, and IL-13 secretion and modulates tissue-resident macrophage (TRM) abundance in chronic pancreatitis. Prkcq knockdown in ILC2s reduced TRM numbers and alleviated pancreatic fibrosis in a mouse model, placing Prkcq upstream of ILC2 cytokine production and downstream TRM accumulation.\",\n      \"method\": \"Single-cell sequencing data analysis; mouse dibutyltin dichloride (DBTC) chronic pancreatitis model; siRNA-mediated Prkcq knockdown in ILC2s; histological assays (H&E, Masson, Sirius Red); cytokine expression analysis\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on knockdown with cytokine readouts, no direct biochemical mechanism established\",\n      \"pmids\": [\"40706949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRKCQ activation mediates anti-adipogenic effects in adipocytes; GLT (Ganoderma lucidum triterpenoids) upregulate PRKCQ expression and inhibit adipogenesis, and deletion of PRKCQ significantly reverses this anti-adipogenic effect, placing PRKCQ as a required mediator of adipogenesis suppression.\",\n      \"method\": \"High-fat diet mouse model; preadipocyte differentiation assays; PRKCQ knockout/deletion; expression analysis of adipogenic genes (PPARγ, C/EBPα, FASN, SCD-1); network pharmacology and machine learning target identification\",\n      \"journal\": \"Foods (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic deletion rescue experiment is suggestive but the mechanistic link between PRKCQ kinase activity and adipogenic transcription factors is not biochemically established; single lab\",\n      \"pmids\": [\"41596924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAP (cold atmospheric plasma) upregulates PRKCQ expression and activates NF-κB signaling to promote melanoblast-to-melanocyte differentiation; mechanistically, PRKCQ upregulation appears to be required upstream of NF-κB activation in this context.\",\n      \"method\": \"Murine vitiligo model (topical hydroquinone); CAP jet treatment; immortalized melanoblast cell line (iMC23); CCK-8 assays; flow cytometry; immunoblot for PRKCQ and NF-κB pathway components; melanogenic gene and melanin synthesis assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative pathway placement, no direct mutagenesis or reconstitution linking PRKCQ to NF-κB in this context\",\n      \"pmids\": [\"42170107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human PRKCQ gene locus was characterized: it spans ~62 kb on chromosome 10p15, is composed of 15 coding exons and 14 introns, and shares conserved intron positions and exon organization with the Drosophila melanogaster dPRKC gene.\",\n      \"method\": \"P1 genomic library cloning; FISH for chromosomal localization; long-range PCR and DNA sequencing to define all exon-intron boundaries\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization by sequencing and FISH, single study but definitive structural result\",\n      \"pmids\": [\"9790596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCQ is not required for spermatogenesis or male fertility in mice. Prkcq knockout males (generated by CRISPR/Cas9) show normal testicular histology, normal spermatogenic cell populations, normal sperm morphology, count, motility, and fertility despite high testicular PRKCQ expression.\",\n      \"method\": \"CRISPR/Cas9 Prkcq knockout mice; histological and immunofluorescence assays; computer-assisted sperm analysis; fertility testing; qPCR for other PKC family members\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean germline KO with comprehensive phenotypic analysis; well-controlled negative result\",\n      \"pmids\": [\"40051302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRKCQ/PKCθ is a serine/threonine kinase whose expression in megakaryocytes is directly controlled at the transcriptional level by RUNX1; in T cells and a subset of triple-negative breast cancer cells its kinase activity drives ERK/MAPK-dependent Rb phosphorylation and cell-cycle progression, suppresses pro-apoptotic Bim to confer chemotherapy resistance, and promotes anoikis resistance and migration; in oral squamous cell carcinoma it sustains autophagic flux by maintaining TRIM22 expression and supporting autophagosome–lysosome fusion; in Schwann cells it modulates c-fos/c-jun pathways during nerve degeneration and regeneration; and it couples to NF-κB signaling in multiple contexts including breast cancer inflammation and melanoblast differentiation, while being dispensable for spermatogenesis in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKCQ encodes PKCθ, a serine/threonine kinase whose expression and catalytic activity couple upstream regulatory inputs to proliferation, survival, and inflammatory signaling across diverse cell types [#1, #2]. In megakaryocytic cells, PRKCQ is a direct transcriptional target of RUNX1, which binds a consensus site in the PRKCQ promoter and drives PKCθ protein expression [#0]. In breast epithelial and triple-negative breast cancer cells, PKCθ kinase activity stimulates ERK/MAPK signaling and Rb phosphorylation to promote cell-cycle progression and growth-factor-independent proliferation, while also conferring anoikis resistance, anchorage-independent survival, and migration [#1, #2]; the same catalytic activity suppresses pro-apoptotic Bim to limit chemotherapy-induced apoptosis, since Bim re-suppression reverses the sensitizing effect of PRKCQ loss [#3]. In oral squamous cell carcinoma, PRKCQ sustains autophagic flux by maintaining TRIM22 expression and supporting lysosomal function and autophagosome–lysosome fusion, with TRIM22 overexpression rescuing the PRKCQ-knockdown phenotype [#6]. Comprehensive germline knockout shows PRKCQ is dispensable for spermatogenesis and male fertility in mice despite high testicular expression [#11]. The human gene spans ~62 kb on chromosome 10p15 across 15 coding exons [#10]. The biochemical events directly linking PKCθ catalysis to ERK, NF-κB, and TRIM22 outputs have not been reconstituted in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the genomic architecture of human PRKCQ, providing the structural foundation for studying its regulation and conservation.\",\n      \"evidence\": \"P1 genomic library cloning, FISH, and long-range PCR sequencing defining all exon-intron boundaries\",\n      \"pmids\": [\"9790596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function or expression control\", \"No isoform or promoter-element characterization\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Answered how PRKCQ expression is controlled in megakaryocytes, identifying RUNX1 as a direct transcriptional driver of the gene.\",\n      \"evidence\": \"ChIP, EMSA, promoter-reporter mutagenesis, siRNA knockdown and overexpression in megakaryocytic cells\",\n      \"pmids\": [\"21252065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of PKCθ in megakaryocytes not defined\", \"Transcriptional control in other lineages unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed PKCθ kinase activity upstream of ERK/MAPK and Rb phosphorylation, showing catalytic activity is required for proliferation and oncogenic transformation phenotypes in breast cells.\",\n      \"evidence\": \"Kinase-active vs kinase-inactive cDNA, AEB071 inhibitor, immunoblot for p-Rb/p-ERK, anoikis and xenograft assays in MCF-10A and TNBC lines\",\n      \"pmids\": [\"27663795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate linking PKCθ to ERK not identified\", \"Mechanism of ERK activation not reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a survival mechanism by which PKCθ catalytic activity suppresses pro-apoptotic Bim to confer chemotherapy resistance in TNBC.\",\n      \"evidence\": \"WT vs kinase-inactive overexpression, knockdown, apoptosis assays, and Bim-suppression rescue in MCF-10A and TNBC lines\",\n      \"pmids\": [\"32600444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical step between PKCθ and Bim regulation unknown\", \"Transcriptional vs post-translational control of Bim unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked Prkcq to Schwann cell proliferation, migration, and apoptosis via β-catenin and c-fos/c-jun pathways during nerve injury.\",\n      \"evidence\": \"Rat sciatic nerve injury model with Schwann cell gain/loss-of-function and pathway immunoblotting\",\n      \"pmids\": [\"34418453\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement based on expression-level readouts without mechanistic reconstitution\", \"Direct kinase targets not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established PRKCQ as an upstream regulator of autophagic flux, acting through TRIM22 to maintain lysosomal function and autophagosome–lysosome fusion in OSCC.\",\n      \"evidence\": \"shRNA knockdown, transcriptomics, autophagic flux and lysosomal assays, TRIM22 overexpression rescue, and xenografts in OSCC cells\",\n      \"pmids\": [\"41764502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRKCQ maintains TRIM22 expression unknown\", \"Whether kinase activity is required not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested the requirement for PRKCQ in spermatogenesis, showing it is dispensable for male fertility despite high testicular expression.\",\n      \"evidence\": \"CRISPR/Cas9 germline knockout mice with histology, sperm analysis, and fertility testing\",\n      \"pmids\": [\"40051302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Possible compensation by other PKC family members not excluded\", \"Testicular function of PKCθ remains undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Prkcq in ILC2 cytokine production and tissue-resident macrophage accumulation during chronic pancreatitis.\",\n      \"evidence\": \"Single-cell sequencing, DBTC pancreatitis mouse model, and siRNA knockdown of Prkcq in ILC2s\",\n      \"pmids\": [\"40706949\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical mechanism established\", \"Pathway placement inferred from cytokine readouts\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified PRKCQ as a required mediator of anti-adipogenic effects and as coupled to NF-κB during melanoblast differentiation.\",\n      \"evidence\": \"High-fat-diet adipogenesis model with PRKCQ deletion, and CAP-treated vitiligo/melanoblast model with NF-κB immunoblotting\",\n      \"pmids\": [\"41596924\", \"42170107\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic link between PRKCQ kinase activity and adipogenic transcription factors not established\", \"Correlative NF-κB placement without mutagenesis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct catalytic substrates of PKCθ that connect it to ERK/MAPK, NF-κB, Bim, and TRIM22 outputs remain unidentified across all contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted phosphorylation substrate reported\", \"No structural model of PKCθ in these signaling complexes\", \"Kinase-activity requirement untested for autophagy and NF-κB phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}