{"gene":"PRKCD","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2021,"finding":"PRKCD kinase activity is required for efficient PRKN-independent mitophagy; PRKCD localizes to mitochondria and facilitates recruitment of ULK1/ATG13 to early autophagic structures. PRKCD is dispensable for PRKN-dependent mitophagy and starvation-induced autophagy.","method":"siRNA screen, kinase-dead mutants, subcellular fractionation/localization, in vitro mitophagy assays, C. elegans and zebrafish knockouts for in vivo validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, kinase-dead mutants, localization, in vivo knockouts in two model organisms), independently supported by follow-up paper (PMID:35001811)","pmids":["34671015","35001811"],"is_preprint":false},{"year":2014,"finding":"PRKCD phosphorylates both FBXO25 and HAX-1, directing nuclear FBXO25 to mitochondrial HAX-1; this triggers SCF(FBXO25)-mediated ubiquitination and degradation of the pro-survival protein HAX-1 following apoptotic stress, thereby initiating an apoptotic response in B cells.","method":"Unbiased substrate screen, phosphorylation assays, Co-IP, epistasis with phosphodegron mutants, Eμ-Myc mouse model and human MCL xenotransplant","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (phosphorylation assay, Co-IP, mutant rescue, two in vivo models) in a single rigorous study","pmids":["25419709"],"is_preprint":false},{"year":2017,"finding":"PRKCD promotes cisplatin-induced kidney tubule cell death by suppressing cytoprotective autophagy; mechanistically, PRKCD phosphorylates AKT, which then phosphorylates MTOR to repress ULK1.","method":"Cell-based assays, pharmacological and genetic manipulation of PRKCD, phosphorylation pathway analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pathway placement via phosphorylation cascade described in a single lab study; abstract is a commentary summarizing prior findings without full methodological detail","pmids":["28059582"],"is_preprint":false},{"year":2023,"finding":"TRIM69 interacts with PRKCD via its B-box domain and catalyzes K48-linked polyubiquitination of PRKCD, leading to its proteasomal degradation; this suppresses BDNF production in a PRKCD-dependent manner, reducing anoikis resistance and metastasis of gastric cancer cells.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, domain mapping, TRIM69 overexpression/knockdown, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mass spectrometry, ubiquitination assay, and in vivo rescue experiments from a single lab","pmids":["37864033"],"is_preprint":false},{"year":2012,"finding":"miR-181a directly targets the 3'-UTR of PRKCD, negatively regulating its expression; reduced PRKCD expression inhibits irradiation-induced apoptosis and decreases G2/M block, conferring radio-resistance in cervical cancer cells.","method":"Luciferase reporter assay, miR-181a mimic/inhibitor transfection, cell culture and mouse xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'-UTR reporter assay plus in vivo xenograft validation, single lab, two orthogonal methods","pmids":["22847611"],"is_preprint":false},{"year":2013,"finding":"miR-181a targets PRKCD 3'-UTR to suppress PRKCD expression, thereby inhibiting cisplatin-induced apoptosis and conferring cisplatin chemoresistance in cervical squamous cell carcinoma cells; silencing PRKCD phenocopies miR-181a overexpression.","method":"Luciferase reporter assay, miR-181a overexpression, PRKCD siRNA knockdown, xenograft model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'-UTR reporter plus in vivo xenograft, corroborated by independent paper (PMID:22847611)","pmids":["24183997"],"is_preprint":false},{"year":2024,"finding":"PRKCD phosphorylated at Y313 (PRKCD_pY313) activates Src (Src_pY419) and p38 MAPK (p38_pT180/pY182), promoting proliferation, invasion, and metastasis in triple-negative breast cancer; Y313F mutation abolishes these effects.","method":"Phosphoproteomic profiling with Superbinder resin, gain-of-function assays, Y313F mutagenesis, xenograft model, kinase pathway analysis","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic identification combined with mutagenesis and in vivo validation, single lab","pmids":["38347536"],"is_preprint":false},{"year":2024,"finding":"PRKCD is identified as a direct molecular partner of CEACAM6 (by BirA-BioID proximity labeling and mass spectrometry) and supports CEACAM6-driven GBC cell migration, with downstream regulation of ERK and AKT signaling.","method":"BirA-BioID proximity labeling, mass spectrometry, in vitro migration assays, in vivo mouse model","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling is less stringent than reciprocal Co-IP; functional rescue not directly attributed to PRKCD alone","pmids":["39468006"],"is_preprint":false},{"year":2024,"finding":"PRKCD promotes ferroptosis in hippocampal neurons by inhibiting the Hippo signaling pathway; PRKCD knockout alleviates sevoflurane-induced neurotoxicity and cognitive impairment, and reverses ferroptosis markers in vivo.","method":"PRKCD knockout mice, western blot, immunofluorescence, transmission electron microscopy, behavioral tests (Morris water maze)","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined cellular phenotype (ferroptosis, Hippo pathway) and behavioral readout, single lab, single study","pmids":["38704083"],"is_preprint":false},{"year":2023,"finding":"Loss of PRKCD in joint tissues prevents cartilage degeneration by inhibiting MMP13 expression; however, loss of PRKCD in sensory neurons exacerbates osteoarthritis-associated hyperalgesia through increased NGF/TrkA and VEGF/VEGFR1 signaling.","method":"Conditional and global Prkcd knockout mice, surgical OA model, immunofluorescence, behavioral pain assessment","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with multiple orthogonal readouts (histopathology, immunofluorescence, behavior), single lab","pmids":["37890601"],"is_preprint":false},{"year":2025,"finding":"SIRT6 demyristoylates ATF2 at K296, reducing nuclear ATF2 localization and consequently decreasing PRKCD expression; reduced PRKCD in turn promotes VE-Cadherin-mediated endothelial barrier integrity (SIRT6/Myr-ATF2/PRKCD/VE-Cadherin axis).","method":"Lysine-myristoylated peptide enrichment, 4D label-free mass spectrometry, gene overexpression/knockdown, SIRT6 KO and double-transgenic mice, molecular approaches","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular and in vivo approaches, but single lab and relatively recent publication","pmids":["40810740"],"is_preprint":false},{"year":2023,"finding":"Foxg1 transcriptionally activates Prkcd expression (confirmed by dual luciferase assay); upregulated PRKCD in the lateral habenula mediates trigeminal neuralgia-associated orofacial pain and anxiety-like behavior in mice.","method":"RNA sequencing, Foxg1-shRNA AAV knockdown, dual luciferase assay, pharmacological PRKCD inhibition in vivo","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus in vivo AAV knockdown and pharmacological inhibition, single lab","pmids":["38085455"],"is_preprint":false},{"year":2026,"finding":"NSUN7 stabilizes and promotes PRKCD translation via 5-methylcytosine modification of PRKCD mRNA; ATF4 transcriptionally activates NSUN7; this ATF4/NSUN7/PRKCD axis mediates sevoflurane-induced mitochondrial fission and neurotoxicity.","method":"Dot blot, RIP assay, dual-luciferase reporter, ChIP assay, NSUN7 KO mice, western blot, flow cytometry","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (RIP, luciferase, ChIP) plus in vivo KO validation, single lab","pmids":["41850512"],"is_preprint":false},{"year":2016,"finding":"PRKCD protein is present and enzymatically active throughout bovine preimplantation embryo development; pharmacological inhibition of PRKCD prevents development beyond the 8-16 cell stage, reduces blastocyst development, lowers inner cell mass-to-trophoblast ratio, decreases basal IFNT expression, and abolishes FGF2-induced IFNT expression, indicating a role in trophoblast gene regulation.","method":"Pharmacological inhibitor (rottlerin), mRNA/protein expression analysis, blastocyst development assays, trophoblast adhesion and proliferation assays","journal":"Reproduction, fertility, and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor only (rottlerin has off-target effects), single lab, bovine model without genetic validation","pmids":["25116760"],"is_preprint":false}],"current_model":"PRKCD is a serine/threonine (and tyrosine-phosphorylatable) kinase that promotes apoptosis by phosphorylating FBXO25 and HAX-1 to trigger HAX-1 degradation, suppresses cytoprotective autophagy by activating AKT-MTOR to repress ULK1, localizes to mitochondria to recruit ULK1/ATG13 and facilitate PRKN-independent mitophagy, activates Src and p38 MAPK downstream of Y313 phosphorylation to drive cancer cell invasion, and is subject to post-translational regulation by K48-linked ubiquitination (via TRIM69), transcriptional control (by Foxg1 and ATF4/NSUN7-mediated mRNA methylation), and miRNA-mediated repression (miR-181a/b, miR-26b-5p targeting its 3'-UTR); collectively these mechanisms position PRKCD as a context-dependent regulator of apoptosis, mitophagy, and cellular stress responses."},"narrative":{"mechanistic_narrative":"PRKCD is a serine/threonine protein kinase that operates as a context-dependent regulator of apoptosis, autophagic/mitophagic flux, and cellular stress responses, with downstream actions dictated by its phosphorylation targets and subcellular localization [PMID:34671015, PMID:35001811, PMID:25419709]. In B cells, PRKCD initiates apoptosis by phosphorylating both the SCF substrate adaptor FBXO25 and the pro-survival protein HAX-1, directing nuclear FBXO25 to mitochondrial HAX-1 to drive SCF(FBXO25)-mediated ubiquitination and degradation of HAX-1 [PMID:25419709]. At mitochondria, PRKCD kinase activity is required for PRKN-independent mitophagy, where it facilitates recruitment of ULK1/ATG13 to early autophagic structures while remaining dispensable for PRKN-dependent mitophagy and starvation-induced autophagy [PMID:34671015, PMID:35001811]. In contrast, in stressed kidney tubule cells PRKCD restrains cytoprotective autophagy through an AKT–MTOR cascade that represses ULK1, thereby promoting cell death [PMID:28059582]. PRKCD activity also drives cancer cell invasion: phosphorylation at Y313 activates Src and p38 MAPK to promote proliferation and metastasis [PMID:38347536]. PRKCD abundance is tightly controlled at multiple levels—K48-linked polyubiquitination by TRIM69 targets it for proteasomal degradation [PMID:37864033], transcriptional input from Foxg1 and the ATF4/NSUN7 (mRNA 5-methylcytosine) axis sets its expression [PMID:38085455, PMID:41850512], and miR-181a represses it via its 3'-UTR [PMID:22847611, PMID:24183997]. Across genetic mouse models PRKCD additionally shapes ferroptosis, MMP13-driven cartilage degeneration, and pain signaling in a tissue-specific manner [PMID:38704083, PMID:37890601].","teleology":[{"year":2014,"claim":"Established a direct molecular route by which PRKCD initiates apoptosis, resolving how a kinase couples to controlled destruction of a pro-survival factor.","evidence":"Unbiased substrate screen, phosphorylation and Co-IP assays, phosphodegron mutants, and Eµ-Myc/MCL xenotransplant models","pmids":["25419709"],"confidence":"High","gaps":["Does not define whether the same FBXO25/HAX-1 axis operates outside B-cell lineages","Upstream activator of PRKCD in this apoptotic context not resolved"]},{"year":2017,"claim":"Placed PRKCD upstream of an AKT–MTOR–ULK1 cascade that suppresses cytoprotective autophagy, framing PRKCD as a pro-death modulator of autophagy in stressed epithelium.","evidence":"Cell-based assays with pharmacological and genetic PRKCD manipulation and phosphorylation pathway analysis in cisplatin-treated kidney tubule cells","pmids":["28059582"],"confidence":"Medium","gaps":["Direct kinase-substrate relationship between PRKCD and AKT not biochemically reconstituted","Summarized largely as commentary without full methodological detail"]},{"year":2021,"claim":"Defined a distinct mitochondrial role for PRKCD in PRKN-independent mitophagy, separating it from canonical PRKN-dependent and starvation-induced autophagy.","evidence":"siRNA screen, kinase-dead mutants, subcellular fractionation, in vitro mitophagy assays, and C. elegans/zebrafish knockouts","pmids":["34671015","35001811"],"confidence":"High","gaps":["Direct PRKCD substrates at the mitochondrion driving ULK1/ATG13 recruitment not identified","Mechanism reconciling pro-mitophagy versus autophagy-suppressing roles unresolved"]},{"year":2023,"claim":"Identified post-translational and transcriptional controls over PRKCD abundance, showing its protein levels and signaling output are set by TRIM69 ubiquitination and Foxg1 transcription.","evidence":"Reciprocal Co-IP/MS, ubiquitination and domain-mapping assays (TRIM69), and RNA-seq plus dual-luciferase and AAV knockdown (Foxg1)","pmids":["37864033","38085455"],"confidence":"Medium","gaps":["Whether TRIM69 regulates PRKCD outside gastric cancer is unknown","How these regulatory inputs are coordinated in a given cell is unaddressed"]},{"year":2024,"claim":"Linked a specific PRKCD tyrosine phosphorylation event to oncogenic signaling, identifying Y313 as the trigger for Src/p38 MAPK activation and invasion.","evidence":"Phosphoproteomic profiling, Y313F mutagenesis, gain-of-function assays, and xenograft models in triple-negative breast cancer","pmids":["38347536"],"confidence":"Medium","gaps":["Kinase responsible for Y313 phosphorylation not identified","Direct versus indirect activation of Src/p38 not distinguished"]},{"year":2024,"claim":"Extended PRKCD's physiological footprint into ferroptosis and tissue-specific pain/cartilage phenotypes through genetic loss-of-function studies.","evidence":"Global and conditional Prkcd knockout mice with histopathology, immunofluorescence, electron microscopy, and behavioral readouts","pmids":["38704083","37890601"],"confidence":"Medium","gaps":["Molecular substrates linking PRKCD to Hippo/ferroptosis and MMP13 regulation not defined","Opposing effects across cell types complicate a unified mechanism"]},{"year":2026,"claim":"Characterized translational and epigenetic control of PRKCD expression via the ATF4/NSUN7 m5C axis, adding mRNA modification to its regulatory layers in neurotoxicity.","evidence":"Dot blot, RIP, dual-luciferase, ChIP assays, and NSUN7 knockout mice","pmids":["41850512"],"confidence":"Medium","gaps":["Generalizability of NSUN7-mediated PRKCD regulation beyond sevoflurane neurotoxicity unknown","Downstream PRKCD substrates driving mitochondrial fission not identified"]},{"year":null,"claim":"How PRKCD's opposing roles—pro-apoptotic versus pro-mitophagy, autophagy-suppressing versus tissue-protective—are selected within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking localization, phosphorylation state, and downstream pathway choice","Direct mitochondrial substrates and the determinants of context-specificity not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,6]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6]}],"complexes":[],"partners":["FBXO25","HAX-1","TRIM69","CEACAM6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q05655","full_name":"Protein kinase C delta type","aliases":["Tyrosine-protein kinase PRKCD","nPKC-delta"],"length_aa":676,"mass_kda":77.5,"function":"Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses (PubMed:21406692, PubMed:21810427). Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction (By similarity). Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis (PubMed:21406692, PubMed:21810427). In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53 (PubMed:21406692, PubMed:21810427). In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53 (PubMed:21406692, PubMed:21810427). In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation (By similarity). Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1 (PubMed:15774464). Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Involved in antifungal immunity by mediating phosphorylation and activation of CARD9 downstream of C-type lectin receptors activation, promoting interaction between CARD9 and BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways (PubMed:19801500). May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA (PubMed:11748588). In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation (PubMed:16940418). Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release (PubMed:19587372). Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin (PubMed:11877440). The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). Phosphorylates ELAVL1 in response to angiotensin-2 treatment (PubMed:18285462). Phosphorylates mitochondrial phospholipid scramblase 3 (PLSCR3), resulting in increased cardiolipin expression on the mitochondrial outer membrane which facilitates apoptosis (PubMed:12649167). Phosphorylates SMPD1 which induces SMPD1 secretion (PubMed:17303575)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Nucleus; Cell membrane; Mitochondrion; Endomembrane system","url":"https://www.uniprot.org/uniprotkb/Q05655/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKCD","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163932","cell_line_id":"CID001246","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"POT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001246","total_profiled":1310},"omim":[{"mim_id":"619874","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 11; PFIC11","url":"https://www.omim.org/entry/619874"},{"mim_id":"618303","title":"CAVEOLAE-ASSOCIATED PROTEIN 3; CAVIN3","url":"https://www.omim.org/entry/618303"},{"mim_id":"615559","title":"AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE III; ALPS3","url":"https://www.omim.org/entry/615559"},{"mim_id":"614854","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 59; LRRC59","url":"https://www.omim.org/entry/614854"},{"mim_id":"610924","title":"RANBP-TYPE AND C3HC4-TYPE ZINC FINGER-CONTAINING 1; RBCK1","url":"https://www.omim.org/entry/610924"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRKCD"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q05655","domains":[{"cath_id":"2.60.40.150","chopping":"3-120","consensus_level":"high","plddt":82.7324,"start":3,"end":120},{"cath_id":"3.30.60.20","chopping":"147-208_227-281","consensus_level":"medium","plddt":82.8338,"start":147,"end":281},{"cath_id":"3.30.200.20","chopping":"344-392_412-431_647-676","consensus_level":"medium","plddt":85.6101,"start":344,"end":676},{"cath_id":"1.10.510.10","chopping":"432-623","consensus_level":"high","plddt":93.8226,"start":432,"end":623}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05655","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q05655-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q05655-F1-predicted_aligned_error_v6.png","plddt_mean":80.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKCD","jax_strain_url":"https://www.jax.org/strain/search?query=PRKCD"},"sequence":{"accession":"Q05655","fasta_url":"https://rest.uniprot.org/uniprotkb/Q05655.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q05655/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05655"}},"corpus_meta":[{"pmid":"22847611","id":"PMC_22847611","title":"MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22847611","citation_count":110,"is_preprint":false},{"pmid":"24183997","id":"PMC_24183997","title":"MicroRNA-181a enhances the chemoresistance of human cervical squamous cell carcinoma to cisplatin by targeting PRKCD.","date":"2013","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/24183997","citation_count":71,"is_preprint":false},{"pmid":"34671015","id":"PMC_34671015","title":"GAK and PRKCD are positive regulators of PRKN-independent mitophagy.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34671015","citation_count":60,"is_preprint":false},{"pmid":"25419709","id":"PMC_25419709","title":"Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.","date":"2014","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25419709","citation_count":53,"is_preprint":false},{"pmid":"33031827","id":"PMC_33031827","title":"CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33031827","citation_count":41,"is_preprint":false},{"pmid":"28059582","id":"PMC_28059582","title":"PRKCD/PKCδ contributes to nephrotoxicity during cisplatin chemotherapy by suppressing autophagy.","date":"2017","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/28059582","citation_count":26,"is_preprint":false},{"pmid":"37864033","id":"PMC_37864033","title":"TRIM69 suppressed the anoikis resistance and metastasis of gastric cancer through ubiquitin‒proteasome-mediated degradation of PRKCD.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37864033","citation_count":25,"is_preprint":false},{"pmid":"26629004","id":"PMC_26629004","title":"MiR181c inhibits ovarian cancer metastasis and progression by targeting PRKCD expression.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26629004","citation_count":24,"is_preprint":false},{"pmid":"8188219","id":"PMC_8188219","title":"Assignment of the protein kinase C delta polypeptide gene (PRKCD) to human chromosome 3 and mouse chromosome 14.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8188219","citation_count":23,"is_preprint":false},{"pmid":"35001811","id":"PMC_35001811","title":"GAK and PRKCD kinases regulate basal mitophagy.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35001811","citation_count":18,"is_preprint":false},{"pmid":"26432191","id":"PMC_26432191","title":"LAMTOR1-PRKCD and NUMA1-SFMBT1 fusion genes identified by RNA sequencing in aneurysmal benign fibrous histiocytoma with t(3;11)(p21;q13).","date":"2015","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26432191","citation_count":18,"is_preprint":false},{"pmid":"38704083","id":"PMC_38704083","title":"Sevoflurane causes neurotoxicity and cognitive impairment by regulating Hippo signaling pathway-mediated ferroptosis via upregulating PRKCD.","date":"2024","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38704083","citation_count":17,"is_preprint":false},{"pmid":"34187243","id":"PMC_34187243","title":"Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD.","date":"2021","source":"International journal of immunopathology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34187243","citation_count":11,"is_preprint":false},{"pmid":"25116760","id":"PMC_25116760","title":"The requirement for protein kinase C delta (PRKCD) during preimplantation bovine embryo development.","date":"2016","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/25116760","citation_count":10,"is_preprint":false},{"pmid":"37794137","id":"PMC_37794137","title":"Phenotypic Variability in PRKCD: a Review of the Literature.","date":"2023","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37794137","citation_count":9,"is_preprint":false},{"pmid":"36279664","id":"PMC_36279664","title":"PRKCD as a potential therapeutic target for chronic obstructive pulmonary disease.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36279664","citation_count":8,"is_preprint":false},{"pmid":"39468006","id":"PMC_39468006","title":"Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39468006","citation_count":7,"is_preprint":false},{"pmid":"38347536","id":"PMC_38347536","title":"Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38347536","citation_count":7,"is_preprint":false},{"pmid":"38128308","id":"PMC_38128308","title":"Activated PRKCD-mediated neutrophil extracellular traps pathway may be the prothrombotic mechanism of neutrophils in polycythemia vera patients based on clinical retrospective analysis and bioinformatics study.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38128308","citation_count":3,"is_preprint":false},{"pmid":"37890601","id":"PMC_37890601","title":"Loss of PKCδ/Prkcd prevents cartilage degeneration in joints but exacerbates hyperalgesia in an experimental osteoarthritis mouse model.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/37890601","citation_count":3,"is_preprint":false},{"pmid":"40810740","id":"PMC_40810740","title":"SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40810740","citation_count":2,"is_preprint":false},{"pmid":"36782298","id":"PMC_36782298","title":"Genetic association of PRKCD and CARD9 polymorphisms with Vogt-Koyanagi-Harada disease in the Chinese Han population.","date":"2023","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36782298","citation_count":2,"is_preprint":false},{"pmid":"38085455","id":"PMC_38085455","title":"Foxg1 Modulation of the Prkcd Gene in the Lateral Habenula Mediates Trigeminal Neuralgia-Associated Anxiety-Like Behaviors in Mice.","date":"2023","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38085455","citation_count":2,"is_preprint":false},{"pmid":"38747331","id":"PMC_38747331","title":"Metastasizing aneurysmal dermatofibroma initially diagnosed as angiosarcoma confirmed by CD63::PRKCD fusion gene detection with nanopore sequencing.","date":"2024","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38747331","citation_count":2,"is_preprint":false},{"pmid":"40965741","id":"PMC_40965741","title":"MiR-26b-5p mediates radioresistance and immunosuppression via targeting PRKCD in non-small cell lung cancer.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40965741","citation_count":1,"is_preprint":false},{"pmid":"40636081","id":"PMC_40636081","title":"Exploring the therapeutic potential of Momordica charantia in targeting protein kinase C delta (PRKCD) for type 2 diabetes mellitus: insights from network pharmacology, molecular docking, and molecular dynamics simulations.","date":"2025","source":"In silico pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40636081","citation_count":1,"is_preprint":false},{"pmid":"40841922","id":"PMC_40841922","title":"Constraint-induced movement therapy combined with mesenchymal stem cell transplantation promotes myelination and functional recovery by inhibiting PRKCD/MEK/ERK pathway in hemiplegic cerebral palsy rats.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40841922","citation_count":0,"is_preprint":false},{"pmid":"25613603","id":"PMC_25613603","title":"[Role of PRKCD and ASK1 in U937 cell differentiation].","date":"2015","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/25613603","citation_count":0,"is_preprint":false},{"pmid":"40415317","id":"PMC_40415317","title":"A Novel Weight Loss Mechanism of Hydroxysafflor Yellow A in Obese Mice: Involvement of Immune Inflammation via Prkcd, Btk, and Vav1 Genes in Adipose Tissue.","date":"2026","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40415317","citation_count":0,"is_preprint":false},{"pmid":"40722182","id":"PMC_40722182","title":"Missense variants in PRKCD: elucidating their potential association with breast cancer.","date":"2025","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/40722182","citation_count":0,"is_preprint":false},{"pmid":"42053760","id":"PMC_42053760","title":"Integrative Multi-Omics and Molecular Simulations Identify PRKCD as a Biological Modulator in Colon Adenocarcinoma: Validation With Phoenix dactylifera Phytochemicals and Comparison With Rottlerin.","date":"2026","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/42053760","citation_count":0,"is_preprint":false},{"pmid":"41850512","id":"PMC_41850512","title":"Sevoflurane activates ATF4/NSUN7/PRKCD axis to induce neurotoxicity and cognitive impairment by promoting neuron mitochondrial fission.","date":"2026","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/41850512","citation_count":0,"is_preprint":false},{"pmid":"41254746","id":"PMC_41254746","title":"\"Benign\" Metastasizing Fibrous Histiocytoma Harboring PRKCD Gene Fusions With Malignant Clinical Course.","date":"2025","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41254746","citation_count":0,"is_preprint":false},{"pmid":"40910294","id":"PMC_40910294","title":"Unlocking New Treatment Horizons for Celiac Disease: PRKCD Revealed as a Promising Target through Mendelian Randomization.","date":"2026","source":"Endocrine, metabolic & immune disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/40910294","citation_count":0,"is_preprint":false},{"pmid":"42170000","id":"PMC_42170000","title":"Expanding the scope of PI3K-δ inhibition: Leniolisib treatment in PRKCD deficiency.","date":"2026","source":"Journal of human immunity","url":"https://pubmed.ncbi.nlm.nih.gov/42170000","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20532,"output_tokens":3428,"usd":0.056508,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10974,"output_tokens":2901,"usd":0.063698,"stage2_stop_reason":"end_turn"},"total_usd":0.120206,"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\": 2021,\n      \"finding\": \"PRKCD kinase activity is required for efficient PRKN-independent mitophagy; PRKCD localizes to mitochondria and facilitates recruitment of ULK1/ATG13 to early autophagic structures. PRKCD is dispensable for PRKN-dependent mitophagy and starvation-induced autophagy.\",\n      \"method\": \"siRNA screen, kinase-dead mutants, subcellular fractionation/localization, in vitro mitophagy assays, C. elegans and zebrafish knockouts for in vivo validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, kinase-dead mutants, localization, in vivo knockouts in two model organisms), independently supported by follow-up paper (PMID:35001811)\",\n      \"pmids\": [\"34671015\", \"35001811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRKCD phosphorylates both FBXO25 and HAX-1, directing nuclear FBXO25 to mitochondrial HAX-1; this triggers SCF(FBXO25)-mediated ubiquitination and degradation of the pro-survival protein HAX-1 following apoptotic stress, thereby initiating an apoptotic response in B cells.\",\n      \"method\": \"Unbiased substrate screen, phosphorylation assays, Co-IP, epistasis with phosphodegron mutants, Eμ-Myc mouse model and human MCL xenotransplant\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (phosphorylation assay, Co-IP, mutant rescue, two in vivo models) in a single rigorous study\",\n      \"pmids\": [\"25419709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRKCD promotes cisplatin-induced kidney tubule cell death by suppressing cytoprotective autophagy; mechanistically, PRKCD phosphorylates AKT, which then phosphorylates MTOR to repress ULK1.\",\n      \"method\": \"Cell-based assays, pharmacological and genetic manipulation of PRKCD, phosphorylation pathway analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pathway placement via phosphorylation cascade described in a single lab study; abstract is a commentary summarizing prior findings without full methodological detail\",\n      \"pmids\": [\"28059582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM69 interacts with PRKCD via its B-box domain and catalyzes K48-linked polyubiquitination of PRKCD, leading to its proteasomal degradation; this suppresses BDNF production in a PRKCD-dependent manner, reducing anoikis resistance and metastasis of gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, domain mapping, TRIM69 overexpression/knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mass spectrometry, ubiquitination assay, and in vivo rescue experiments from a single lab\",\n      \"pmids\": [\"37864033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-181a directly targets the 3'-UTR of PRKCD, negatively regulating its expression; reduced PRKCD expression inhibits irradiation-induced apoptosis and decreases G2/M block, conferring radio-resistance in cervical cancer cells.\",\n      \"method\": \"Luciferase reporter assay, miR-181a mimic/inhibitor transfection, cell culture and mouse xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'-UTR reporter assay plus in vivo xenograft validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"22847611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-181a targets PRKCD 3'-UTR to suppress PRKCD expression, thereby inhibiting cisplatin-induced apoptosis and conferring cisplatin chemoresistance in cervical squamous cell carcinoma cells; silencing PRKCD phenocopies miR-181a overexpression.\",\n      \"method\": \"Luciferase reporter assay, miR-181a overexpression, PRKCD siRNA knockdown, xenograft model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'-UTR reporter plus in vivo xenograft, corroborated by independent paper (PMID:22847611)\",\n      \"pmids\": [\"24183997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCD phosphorylated at Y313 (PRKCD_pY313) activates Src (Src_pY419) and p38 MAPK (p38_pT180/pY182), promoting proliferation, invasion, and metastasis in triple-negative breast cancer; Y313F mutation abolishes these effects.\",\n      \"method\": \"Phosphoproteomic profiling with Superbinder resin, gain-of-function assays, Y313F mutagenesis, xenograft model, kinase pathway analysis\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic identification combined with mutagenesis and in vivo validation, single lab\",\n      \"pmids\": [\"38347536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCD is identified as a direct molecular partner of CEACAM6 (by BirA-BioID proximity labeling and mass spectrometry) and supports CEACAM6-driven GBC cell migration, with downstream regulation of ERK and AKT signaling.\",\n      \"method\": \"BirA-BioID proximity labeling, mass spectrometry, in vitro migration assays, in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling is less stringent than reciprocal Co-IP; functional rescue not directly attributed to PRKCD alone\",\n      \"pmids\": [\"39468006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCD promotes ferroptosis in hippocampal neurons by inhibiting the Hippo signaling pathway; PRKCD knockout alleviates sevoflurane-induced neurotoxicity and cognitive impairment, and reverses ferroptosis markers in vivo.\",\n      \"method\": \"PRKCD knockout mice, western blot, immunofluorescence, transmission electron microscopy, behavioral tests (Morris water maze)\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined cellular phenotype (ferroptosis, Hippo pathway) and behavioral readout, single lab, single study\",\n      \"pmids\": [\"38704083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of PRKCD in joint tissues prevents cartilage degeneration by inhibiting MMP13 expression; however, loss of PRKCD in sensory neurons exacerbates osteoarthritis-associated hyperalgesia through increased NGF/TrkA and VEGF/VEGFR1 signaling.\",\n      \"method\": \"Conditional and global Prkcd knockout mice, surgical OA model, immunofluorescence, behavioral pain assessment\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with multiple orthogonal readouts (histopathology, immunofluorescence, behavior), single lab\",\n      \"pmids\": [\"37890601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT6 demyristoylates ATF2 at K296, reducing nuclear ATF2 localization and consequently decreasing PRKCD expression; reduced PRKCD in turn promotes VE-Cadherin-mediated endothelial barrier integrity (SIRT6/Myr-ATF2/PRKCD/VE-Cadherin axis).\",\n      \"method\": \"Lysine-myristoylated peptide enrichment, 4D label-free mass spectrometry, gene overexpression/knockdown, SIRT6 KO and double-transgenic mice, molecular approaches\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular and in vivo approaches, but single lab and relatively recent publication\",\n      \"pmids\": [\"40810740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Foxg1 transcriptionally activates Prkcd expression (confirmed by dual luciferase assay); upregulated PRKCD in the lateral habenula mediates trigeminal neuralgia-associated orofacial pain and anxiety-like behavior in mice.\",\n      \"method\": \"RNA sequencing, Foxg1-shRNA AAV knockdown, dual luciferase assay, pharmacological PRKCD inhibition in vivo\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus in vivo AAV knockdown and pharmacological inhibition, single lab\",\n      \"pmids\": [\"38085455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NSUN7 stabilizes and promotes PRKCD translation via 5-methylcytosine modification of PRKCD mRNA; ATF4 transcriptionally activates NSUN7; this ATF4/NSUN7/PRKCD axis mediates sevoflurane-induced mitochondrial fission and neurotoxicity.\",\n      \"method\": \"Dot blot, RIP assay, dual-luciferase reporter, ChIP assay, NSUN7 KO mice, western blot, flow cytometry\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (RIP, luciferase, ChIP) plus in vivo KO validation, single lab\",\n      \"pmids\": [\"41850512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRKCD protein is present and enzymatically active throughout bovine preimplantation embryo development; pharmacological inhibition of PRKCD prevents development beyond the 8-16 cell stage, reduces blastocyst development, lowers inner cell mass-to-trophoblast ratio, decreases basal IFNT expression, and abolishes FGF2-induced IFNT expression, indicating a role in trophoblast gene regulation.\",\n      \"method\": \"Pharmacological inhibitor (rottlerin), mRNA/protein expression analysis, blastocyst development assays, trophoblast adhesion and proliferation assays\",\n      \"journal\": \"Reproduction, fertility, and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor only (rottlerin has off-target effects), single lab, bovine model without genetic validation\",\n      \"pmids\": [\"25116760\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRKCD is a serine/threonine (and tyrosine-phosphorylatable) kinase that promotes apoptosis by phosphorylating FBXO25 and HAX-1 to trigger HAX-1 degradation, suppresses cytoprotective autophagy by activating AKT-MTOR to repress ULK1, localizes to mitochondria to recruit ULK1/ATG13 and facilitate PRKN-independent mitophagy, activates Src and p38 MAPK downstream of Y313 phosphorylation to drive cancer cell invasion, and is subject to post-translational regulation by K48-linked ubiquitination (via TRIM69), transcriptional control (by Foxg1 and ATF4/NSUN7-mediated mRNA methylation), and miRNA-mediated repression (miR-181a/b, miR-26b-5p targeting its 3'-UTR); collectively these mechanisms position PRKCD as a context-dependent regulator of apoptosis, mitophagy, and cellular stress responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKCD is a serine/threonine protein kinase that operates as a context-dependent regulator of apoptosis, autophagic/mitophagic flux, and cellular stress responses, with downstream actions dictated by its phosphorylation targets and subcellular localization [#0, #1]. In B cells, PRKCD initiates apoptosis by phosphorylating both the SCF substrate adaptor FBXO25 and the pro-survival protein HAX-1, directing nuclear FBXO25 to mitochondrial HAX-1 to drive SCF(FBXO25)-mediated ubiquitination and degradation of HAX-1 [#1]. At mitochondria, PRKCD kinase activity is required for PRKN-independent mitophagy, where it facilitates recruitment of ULK1/ATG13 to early autophagic structures while remaining dispensable for PRKN-dependent mitophagy and starvation-induced autophagy [#0]. In contrast, in stressed kidney tubule cells PRKCD restrains cytoprotective autophagy through an AKT–MTOR cascade that represses ULK1, thereby promoting cell death [#2]. PRKCD activity also drives cancer cell invasion: phosphorylation at Y313 activates Src and p38 MAPK to promote proliferation and metastasis [#6]. PRKCD abundance is tightly controlled at multiple levels—K48-linked polyubiquitination by TRIM69 targets it for proteasomal degradation [#3], transcriptional input from Foxg1 and the ATF4/NSUN7 (mRNA 5-methylcytosine) axis sets its expression [#11, #12], and miR-181a represses it via its 3'-UTR [#4, #5]. Across genetic mouse models PRKCD additionally shapes ferroptosis, MMP13-driven cartilage degeneration, and pain signaling in a tissue-specific manner [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a direct molecular route by which PRKCD initiates apoptosis, resolving how a kinase couples to controlled destruction of a pro-survival factor.\",\n      \"evidence\": \"Unbiased substrate screen, phosphorylation and Co-IP assays, phosphodegron mutants, and Eµ-Myc/MCL xenotransplant models\",\n      \"pmids\": [\"25419709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define whether the same FBXO25/HAX-1 axis operates outside B-cell lineages\", \"Upstream activator of PRKCD in this apoptotic context not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed PRKCD upstream of an AKT–MTOR–ULK1 cascade that suppresses cytoprotective autophagy, framing PRKCD as a pro-death modulator of autophagy in stressed epithelium.\",\n      \"evidence\": \"Cell-based assays with pharmacological and genetic PRKCD manipulation and phosphorylation pathway analysis in cisplatin-treated kidney tubule cells\",\n      \"pmids\": [\"28059582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate relationship between PRKCD and AKT not biochemically reconstituted\", \"Summarized largely as commentary without full methodological detail\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a distinct mitochondrial role for PRKCD in PRKN-independent mitophagy, separating it from canonical PRKN-dependent and starvation-induced autophagy.\",\n      \"evidence\": \"siRNA screen, kinase-dead mutants, subcellular fractionation, in vitro mitophagy assays, and C. elegans/zebrafish knockouts\",\n      \"pmids\": [\"34671015\", \"35001811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PRKCD substrates at the mitochondrion driving ULK1/ATG13 recruitment not identified\", \"Mechanism reconciling pro-mitophagy versus autophagy-suppressing roles unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-translational and transcriptional controls over PRKCD abundance, showing its protein levels and signaling output are set by TRIM69 ubiquitination and Foxg1 transcription.\",\n      \"evidence\": \"Reciprocal Co-IP/MS, ubiquitination and domain-mapping assays (TRIM69), and RNA-seq plus dual-luciferase and AAV knockdown (Foxg1)\",\n      \"pmids\": [\"37864033\", \"38085455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM69 regulates PRKCD outside gastric cancer is unknown\", \"How these regulatory inputs are coordinated in a given cell is unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked a specific PRKCD tyrosine phosphorylation event to oncogenic signaling, identifying Y313 as the trigger for Src/p38 MAPK activation and invasion.\",\n      \"evidence\": \"Phosphoproteomic profiling, Y313F mutagenesis, gain-of-function assays, and xenograft models in triple-negative breast cancer\",\n      \"pmids\": [\"38347536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Y313 phosphorylation not identified\", \"Direct versus indirect activation of Src/p38 not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended PRKCD's physiological footprint into ferroptosis and tissue-specific pain/cartilage phenotypes through genetic loss-of-function studies.\",\n      \"evidence\": \"Global and conditional Prkcd knockout mice with histopathology, immunofluorescence, electron microscopy, and behavioral readouts\",\n      \"pmids\": [\"38704083\", \"37890601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrates linking PRKCD to Hippo/ferroptosis and MMP13 regulation not defined\", \"Opposing effects across cell types complicate a unified mechanism\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized translational and epigenetic control of PRKCD expression via the ATF4/NSUN7 m5C axis, adding mRNA modification to its regulatory layers in neurotoxicity.\",\n      \"evidence\": \"Dot blot, RIP, dual-luciferase, ChIP assays, and NSUN7 knockout mice\",\n      \"pmids\": [\"41850512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability of NSUN7-mediated PRKCD regulation beyond sevoflurane neurotoxicity unknown\", \"Downstream PRKCD substrates driving mitochondrial fission not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRKCD's opposing roles—pro-apoptotic versus pro-mitophagy, autophagy-suppressing versus tissue-protective—are selected within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking localization, phosphorylation state, and downstream pathway choice\", \"Direct mitochondrial substrates and the determinants of context-specificity not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FBXO25\", \"HAX-1\", \"TRIM69\", \"CEACAM6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}