{"gene":"PRKCSH","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"Glucosidase II is a two-subunit enzyme; the beta subunit (encoded by PRKCSH, then called 80K-H) is a non-catalytic, HDEL-containing subunit tightly associated with the catalytic alpha subunit. The beta subunit contains a C-terminal HDEL ER-retention signal and is responsible for ER localization of the enzyme complex.","method":"Biochemical purification of glucosidase II from rat liver, peptide sequencing, cDNA identification, and yeast gene disruption experiments","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted enzyme complex, subunit sequencing, functional yeast KO, foundational paper with >197 citations","pmids":["8910335"],"is_preprint":false},{"year":1996,"finding":"80K-H (PRKCSH protein) was identified as a tyrosine-phosphorylated substrate (p90) in FGF-stimulated fibroblasts and was found to bind specifically to the SH2/SH3 adaptor protein GRB-2, placing 80K-H in the FGF receptor signaling pathway.","method":"2D-PAGE microsequencing, anti-phosphotyrosine immunoprecipitation, GST-GRB2 pulldown, Western blotting","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and pulldown, single lab","pmids":["8621453"],"is_preprint":false},{"year":1996,"finding":"The AGE-receptor component p90 is identical to 80K-H (PRKCSH protein); OST-48 (p60) and 80K-H (p90) together mediate AGE binding on cell surfaces. Immunoprecipitated OST-48 from rough ER fractions exhibited AGE binding, and immune IgG to recombinant 80K-H inhibited AGE-BSA binding to cell membranes.","method":"N-terminal sequencing, AGE-ligand binding assays, Western blotting, immunoprecipitation, flow cytometry, immunostaining, antibody inhibition assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study; single lab","pmids":["8855306"],"is_preprint":false},{"year":2003,"finding":"Germline loss-of-function mutations in PRKCSH (splice-site mutations) cause autosomal dominant polycystic liver disease (PCLD), establishing PRKCSH as a disease gene. The protein, named hepatocystin, is predicted to localize to the ER.","method":"Genetic linkage mapping, mutation analysis by sequencing, disease segregation analysis in four Dutch families","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via disease linkage, replicated across multiple families, independently confirmed by second lab","pmids":["12577059","12529853"],"is_preprint":false},{"year":2003,"finding":"PRKCSH encodes the noncatalytic beta-subunit of glucosidase II, a protein highly conserved across tissues, containing an LDLa domain, two EF-hand domains, and a C-terminal HDEL ER-retention sequence, with proposed roles in N-glycosylation regulation and FGF receptor signal transduction.","method":"Sequence analysis, DHPLC heteroduplex analysis, direct sequencing for mutation detection, domain annotation","journal":"American Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and sequence-based functional annotation; independently corroborated by Drenth et al.","pmids":["12529853"],"is_preprint":false},{"year":2004,"finding":"80K-H (PRKCSH protein) acts as a Ca2+ sensor that directly interacts with and regulates the epithelial Ca2+ channel TRPV5. Ca2+ binding via two EF-hand domains in 80K-H modulates TRPV5 channel activity; inactivation of the EF-hands abolished Ca2+ binding and altered TRPV5-mediated Ca2+ current and sensitivity to intracellular Ca2+. The HDEL and acidic glutamic stretch domains are also required for full TRPV5 regulation. Both proteins co-localize in kidney.","method":"cDNA microarray identification, co-immunoprecipitation, co-localization (immunofluorescence), Ca2+-binding assay, electrophysiology with domain mutants","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct Ca2+-binding assay, mutagenesis of EF-hands, electrophysiology, multiple orthogonal methods","pmids":["15100231"],"is_preprint":false},{"year":2005,"finding":"80K-H (PRKCSH protein) interacts with PKCzeta and munc18c in an insulin-dependent manner, forming a trimeric complex (PKCzeta–80K-H–munc18c) that promotes GLUT4 vesicle translocation to the plasma membrane. Overexpression of 80K-H mimicked insulin's effect on glucose uptake and GLUT4 translocation, proportional to its ability to associate with munc18c.","method":"Yeast two-hybrid screen, GST pulldown, endogenous co-immunoprecipitation from adipocytes and myotubes, glucose uptake assay, GLUT4 translocation assay","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP in multiple cell types, functional overexpression assay, multiple orthogonal methods","pmids":["15707389"],"is_preprint":false},{"year":2008,"finding":"80K-H (PRKCSH protein) directly interacts with the C-terminal tail of IP3 receptor type 1 (IP3R1), co-localizes with IP3R1 in COS-7 cells and hippocampal neurons, and directly enhances IP3-induced Ca2+ release from ER microsomes. 80K-H also regulates ATP-induced Ca2+ release in living cells.","method":"Yeast two-hybrid screen, in vitro direct binding assay, co-immunoprecipitation, immunocytochemistry/immunohistochemistry, Ca2+ release assay with purified recombinant 80K-H","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstituted Ca2+ release assay with purified protein plus co-IP and co-localization","pmids":["18990696"],"is_preprint":false},{"year":2008,"finding":"Hepatocystin (PRKCSH protein) localizes predominantly to the ER in liver cells (both hepatocytes and bile duct epithelia). In PCLD patients with PRKCSH mutations, cyst epithelium lacks hepatocystin expression (consistent with a two-hit/loss-of-function mechanism), while Sec63p is still expressed in all cysts. Hepatocystin and Sec63p do not interact with each other.","method":"Cell fractionation, immunofluorescence, immunohistochemistry in fetal and adult liver and PCLD cyst tissue","journal":"Histochemistry and Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with functional inference; single lab","pmids":["18224332"],"is_preprint":false},{"year":2010,"finding":"PRKCSH (hepatocystin) functions as a chaperone-like molecule that binds the C-terminal domain of TRPP2/polycystin-2 within the ER and protects TRPP2 from HERP-mediated ubiquitination and ER-associated degradation (ERAD). PRKCSH interacts with Herp and inhibits Herp-mediated ubiquitination of TRPP2. Over-expression or depletion of PRKCSH in zebrafish embryos phenocopies TRPP2 perturbation (pronephric cysts, body curvature, situs inversus), indicating a shared signaling pathway.","method":"Co-immunoprecipitation, co-localization, zebrafish overexpression/morpholino knockdown, ubiquitination assay, genetic epistasis in zebrafish","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 — co-IP, ubiquitination assay, in vivo genetic epistasis in zebrafish with multiple orthogonal methods","pmids":["19801576"],"is_preprint":false},{"year":2012,"finding":"TRIM67 E3 ubiquitin ligase interacts with 80K-H (PRKCSH protein) and promotes its proteasomal degradation. Ectopic TRIM67 expression reduces endogenous 80K-H levels, attenuates cell proliferation, and enhances neuritogenesis in N1E-115 neuroblastoma cells; 80K-H knockdown phenocopies TRIM67 overexpression, indicating 80K-H is a downstream effector of TRIM67 in Ras-mediated signaling and neural differentiation.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, cell proliferation assay, neuritogenesis assay","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional knockdown/OE with phenotypic readout; single lab","pmids":["22337885"],"is_preprint":false},{"year":2013,"finding":"Hepatocystin (PRKCSH protein) interacts with HBx protein of hepatitis B virus via its mannose 6-phosphate receptor homology domain (aa 419–525) binding to HBx C-terminus (aa 110–154). Hepatocystin overexpression accelerates HBx degradation via a ubiquitin-independent proteasome pathway, inhibiting HBV DNA replication and HBs antigen expression.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation, Western blot, immunocytochemistry, domain mapping, proteasome/translation inhibitor assays, HBV replication assay","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, domain mapping, functional assay; single lab","pmids":["23644164"],"is_preprint":false},{"year":2019,"finding":"PRKCSH functions as a selective regulator of the IRE1α branch of the unfolded protein response (UPR). PRKCSH directly interacts with IRE1α and boosts its ER stress-mediated autophosphorylation and oligomerization, leading to selective activation of IRE1α/XBP1 signaling. This promotes expression of tumor-promoting factors and confers tumor cell resistance to ER stress.","method":"Co-immunoprecipitation, autophosphorylation assay, oligomerization assay, PRKCSH knockdown/overexpression, XBP1 target gene expression analysis, in vivo tumor models","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — direct interaction + functional phosphorylation/oligomerization assays + in vivo validation; multiple methods","pmids":["31320625"],"is_preprint":false},{"year":2024,"finding":"PRKCSH interacts with IGF1R and extends its protein half-life (stabilizes it), thereby boosting IGF1R oncogenic signaling in lung cancer cells. The PRKCSH-IGF1R axis impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, promoting TNFSF resistance. PRKCSH deficiency augments NK cell-mediated antitumor killing in a xenograft model.","method":"Co-immunoprecipitation, protein half-life assay, caspase activation assay, Mcl-1 expression analysis, siRNA knockdown, tumor xenograft model with NK cells","journal":"Experimental & Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus protein stability assay and in vivo xenograft; single lab","pmids":["38200153"],"is_preprint":false},{"year":2025,"finding":"PRKCSH inhibition in colorectal cancer cells sensitizes them to ionizing radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduces p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation, impairing DNA repair and thus reducing radioresistance.","method":"PRKCSH knockdown, clonogenic survival assay, apoptosis assay, DNA damage repair assay, p53 ubiquitination assay, IRE1α/XBP1s pathway analysis, patient-derived organoids, tumor xenograft","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement with multiple assays; single lab","pmids":["40189587"],"is_preprint":false},{"year":2025,"finding":"PRKCSH deficiency in lung adenocarcinoma cells leads to exaggerated IRE1α activation under ER stress (increased XBP1s and p-JNK), suppresses IL-6 and IL-8 secretion, promotes M1 macrophage polarization (increased CD86+ macrophages), and enhances susceptibility to ER stress-induced apoptosis and ferroptosis while impairing autophagy.","method":"CRISPR/Cas9 KO, cytokine profiling, macrophage co-culture, flow cytometry, zebrafish xenograft, clinical pleural effusion sample analysis","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with multiple functional readouts and in vivo zebrafish validation; single lab","pmids":["41350724"],"is_preprint":false},{"year":2024,"finding":"Myoclonin1 (EFHC1 protein) interacts with PRKCSH (80K-H), which itself interacts with IP3R1, placing PRKCSH at the intersection of a myoclonin1–PRKCSH–IP3R complex that modulates ER Ca2+ homeostasis and IP3-induced Ca2+ release.","method":"Co-immunoprecipitation, Ca2+ measurement in Efhc1-deficient mouse cells, IP3-induced Ca2+ release assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — co-IP interaction; preprint, single lab","pmids":["bio_10.1101_2024.07.01.601633"],"is_preprint":true}],"current_model":"PRKCSH encodes hepatocystin/80K-H, the non-catalytic beta subunit of ER glucosidase II that retains the enzyme complex in the ER via its HDEL signal; it acts as a Ca2+-sensing chaperone-like regulator that protects client glycoproteins (e.g., TRPP2) from HERP-mediated ERAD, modulates IP3R1-dependent and TRPV5-dependent Ca2+ signaling via EF-hand domains, promotes GLUT4 vesicle trafficking through a PKCzeta–80K-H–munc18c complex, and selectively boosts IRE1α autophosphorylation and oligomerization to activate the XBP1 branch of the UPR, while loss-of-function germline mutations cause autosomal dominant polycystic liver disease through a two-hit cystogenesis mechanism."},"narrative":{"teleology":[{"year":1996,"claim":"The identity of PRKCSH as the non-catalytic beta subunit of glucosidase II established its core enzymatic partnership and ER-retention mechanism, answering how glucosidase II is localized and assembled in the ER.","evidence":"Biochemical purification from rat liver, peptide sequencing, cDNA cloning, and yeast gene disruption","pmids":["8910335"],"confidence":"High","gaps":["Catalytic contribution of the beta subunit to trimming activity not defined","Structural basis of alpha-beta interaction unknown"]},{"year":1996,"claim":"Parallel findings placed 80K-H as a signaling-competent molecule — a tyrosine-phosphorylated FGF-receptor substrate binding GRB2 and a component of AGE receptor complexes — suggesting roles beyond glucosidase II scaffolding.","evidence":"Phosphotyrosine immunoprecipitation, GST-GRB2 pulldown (FGF signaling); AGE-ligand binding, antibody inhibition assays (AGE receptor)","pmids":["8621453","8855306"],"confidence":"Medium","gaps":["FGF/GRB2 interaction not confirmed with reciprocal endogenous IP","Physiological relevance of AGE binding not established in vivo","Relationship between ER-resident function and cell-surface signaling roles unclear"]},{"year":2003,"claim":"Identification of PRKCSH germline mutations in polycystic liver disease families established it as a disease gene and implied that loss of hepatocystin's ER functions drives cystogenesis.","evidence":"Linkage mapping and mutation analysis across multiple Dutch families, independently confirmed by a second group","pmids":["12577059","12529853"],"confidence":"High","gaps":["Molecular mechanism linking glucosidase II beta loss to cholangiocyte cyst formation not defined","Nature of second hit not characterized"]},{"year":2004,"claim":"Demonstration that PRKCSH's EF-hand domains sense Ca²⁺ and directly regulate the TRPV5 channel established a Ca²⁺-sensor function independent of its glucosidase II role.","evidence":"Co-IP, Ca²⁺-binding assays with EF-hand mutants, electrophysiology of TRPV5 currents","pmids":["15100231"],"confidence":"High","gaps":["Whether Ca²⁺ sensing and glucosidase II scaffolding are mutually exclusive activities is unknown","In vivo renal Ca²⁺ phenotype in PRKCSH-deficient animals not tested"]},{"year":2005,"claim":"Discovery of a PKCζ–80K-H–munc18c trimeric complex that promotes GLUT4 translocation revealed PRKCSH as an adaptor in insulin-stimulated glucose uptake.","evidence":"Yeast two-hybrid, reciprocal co-IP from adipocytes and myotubes, GLUT4 translocation and glucose uptake assays","pmids":["15707389"],"confidence":"High","gaps":["Structural basis of trimeric complex assembly unknown","Relevance to PCLD pathogenesis not addressed"]},{"year":2008,"claim":"Direct enhancement of IP3-induced Ca²⁺ release by purified 80K-H binding to IP3R1 established PRKCSH as a positive modulator of ER Ca²⁺ store mobilization, and ER localization of hepatocystin in cholangiocytes with loss in PCLD cysts supported a two-hit cystogenesis model.","evidence":"In vitro reconstituted Ca²⁺ release assay with purified protein, co-IP, immunohistochemistry of PCLD cyst tissue","pmids":["18990696","18224332"],"confidence":"High","gaps":["Whether IP3R1 modulation is Ca²⁺-EF-hand-dependent not tested","Two-hit mechanism not genetically proven at the somatic level"]},{"year":2010,"claim":"PRKCSH was shown to protect TRPP2/polycystin-2 from HERP-mediated ubiquitination and ERAD, and zebrafish epistasis phenocopied polycystin-2 perturbation, providing a mechanistic link between PRKCSH loss and cystic disease.","evidence":"Co-IP, ubiquitination assays, zebrafish morpholino/overexpression with pronephric cyst and laterality phenotypes","pmids":["19801576"],"confidence":"High","gaps":["Whether glucosidase II trimming activity is required for the TRPP2-protective function is unknown","Mammalian in vivo confirmation lacking"]},{"year":2012,"claim":"Identification of TRIM67-mediated proteasomal degradation of 80K-H, with phenotypic consequences for neuritogenesis, revealed upstream regulation of PRKCSH protein levels in neural differentiation.","evidence":"Co-IP, siRNA knockdown, TRIM67 overexpression, proliferation and neuritogenesis assays in neuroblastoma cells","pmids":["22337885"],"confidence":"Medium","gaps":["Ubiquitin site(s) on 80K-H not mapped","In vivo neuronal phenotype of PRKCSH loss not examined","Single cell line (N1E-115)"]},{"year":2019,"claim":"PRKCSH was established as a selective activator of the IRE1α/XBP1 branch of the UPR through direct interaction with IRE1α and promotion of its autophosphorylation and oligomerization, linking PRKCSH to ER-stress signaling and tumor biology.","evidence":"Co-IP, autophosphorylation and oligomerization assays, PRKCSH knockdown/overexpression, XBP1 target gene profiling, in vivo tumor models","pmids":["31320625"],"confidence":"High","gaps":["Whether IRE1α interaction is glycan-dependent or direct protein–protein is unclear","Relationship between glucosidase II activity and UPR regulation not dissected"]},{"year":2024,"claim":"PRKCSH stabilizes IGF1R protein to boost oncogenic survival signaling, impairing caspase-8 activation and conferring TNFSF resistance, and its loss enhances NK cell-mediated tumor killing, expanding its tumor-promoting functions beyond UPR modulation.","evidence":"Co-IP, protein half-life assay, caspase activation assays, xenograft model with NK cells","pmids":["38200153"],"confidence":"Medium","gaps":["Whether IGF1R stabilization is glycan-processing-dependent not tested","Single cancer type (lung)","NK cell killing mechanism not fully dissected"]},{"year":2025,"claim":"In colorectal and lung cancer cells, PRKCSH inhibition was shown to sensitize tumors to ionizing radiation and ferroptosis through exaggerated IRE1α activation, p53 stabilization, and altered macrophage polarization, consolidating PRKCSH as a multifaceted regulator of tumor-immune and stress-response crosstalk.","evidence":"PRKCSH knockdown and CRISPR KO, clonogenic survival, apoptosis, DNA repair assays, cytokine profiling, macrophage co-culture, patient-derived organoids, xenograft models","pmids":["40189587","41350724"],"confidence":"Medium","gaps":["Therapeutic window for PRKCSH inhibition not defined","Contribution of glucosidase II catalytic activity versus non-catalytic functions in these phenotypes not separated"]},{"year":null,"claim":"A central unresolved question is whether the diverse functions of PRKCSH — glucosidase II scaffolding, Ca²⁺ sensing, ERAD protection, IRE1α activation, and receptor stabilization — represent independent activities of distinct domains or are mechanistically coupled through its glycan-processing role.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the full glucosidase II complex with client substrates","Domain-specific separation-of-function mutants for glucosidase II versus signaling roles not systematically generated","Conditional knockout mouse model to separate hepatic versus extrahepatic functions not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,12]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,9,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6,7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,13,14,15]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,6,7]}],"complexes":["Glucosidase II (alpha-beta heterodimer)","PKCζ–80K-H–munc18c complex"],"partners":["GIIΑ (GANAB)","TRPV5","ITPR1","PKD2","PRKCZ","MUNC18C (STXBP3)","IRE1Α (ERN1)","IGF1R"],"other_free_text":[]},"mechanistic_narrative":"PRKCSH encodes the non-catalytic beta subunit of ER glucosidase II, functioning as an ER-resident regulatory and chaperone-like glycoprotein that integrates N-glycan processing with Ca²⁺ signaling, protein quality control, and the unfolded protein response. Its C-terminal HDEL signal retains the glucosidase II holoenzyme in the ER, while its EF-hand domains sense Ca²⁺ to regulate ion channels including TRPV5 and IP3R1, and it protects client glycoproteins such as TRPP2 from HERP-mediated ERAD [PMID:8910335, PMID:15100231, PMID:18990696, PMID:19801576]. PRKCSH selectively promotes IRE1α autophosphorylation and oligomerization, activating the XBP1 branch of the UPR; in cancer contexts this confers ER-stress resistance and modulates tumor immune evasion via cytokine and apoptotic pathways [PMID:31320625, PMID:40189587, PMID:41350724]. Germline loss-of-function mutations in PRKCSH cause autosomal dominant polycystic liver disease through a two-hit cystogenesis mechanism [PMID:12577059, PMID:12529853]."},"prefetch_data":{"uniprot":{"accession":"P14314","full_name":"Glucosidase 2 subunit beta","aliases":["80K-H protein","Glucosidase II subunit beta","Protein kinase C substrate 60.1 kDa protein heavy chain","PKCSH"],"length_aa":528,"mass_kda":59.4,"function":"Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins (PubMed:10929008). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity)","subcellular_location":"Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P14314/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKCSH","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRKCSH","total_profiled":1310},"omim":[{"mim_id":"617874","title":"POLYCYSTIC LIVER DISEASE 3 WITH OR WITHOUT KIDNEY CYSTS; PCLD3","url":"https://www.omim.org/entry/617874"},{"mim_id":"617004","title":"POLYCYSTIC LIVER DISEASE 2 WITH OR WITHOUT KIDNEY CYSTS; PCLD2","url":"https://www.omim.org/entry/617004"},{"mim_id":"609214","title":"SEC61 TRANSLOCON, BETA SUBUNIT; SEC61B","url":"https://www.omim.org/entry/609214"},{"mim_id":"608648","title":"SEC63 HOMOLOG, PROTEIN TRANSLOCATION REGULATOR; SEC63","url":"https://www.omim.org/entry/608648"},{"mim_id":"608103","title":"ALG8 ALPHA-1,3-GLUCOSYLTRANSFERASE; ALG8","url":"https://www.omim.org/entry/608103"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRKCSH"},"hgnc":{"alias_symbol":["VASAP-60","GIIB","PKCSH","80K-H","AGE-R2","GIIbeta","GluIIbeta"],"prev_symbol":["G19P1","PCLD","PLD1"]},"alphafold":{"accession":"P14314","domains":[{"cath_id":"-","chopping":"16-114","consensus_level":"medium","plddt":94.7155,"start":16,"end":114},{"cath_id":"-","chopping":"120-278","consensus_level":"medium","plddt":91.8436,"start":120,"end":278},{"cath_id":"2.70.130.10","chopping":"410-512","consensus_level":"high","plddt":96.1656,"start":410,"end":512}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14314","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14314-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14314-F1-predicted_aligned_error_v6.png","plddt_mean":84.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKCSH","jax_strain_url":"https://www.jax.org/strain/search?query=PRKCSH"},"sequence":{"accession":"P14314","fasta_url":"https://rest.uniprot.org/uniprotkb/P14314.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14314/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14314"}},"corpus_meta":[{"pmid":"8855306","id":"PMC_8855306","title":"Molecular identity and cellular distribution of advanced glycation endproduct receptors: relationship of p60 to OST-48 and p90 to 80K-H membrane proteins.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8855306","citation_count":299,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12577059","id":"PMC_12577059","title":"Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12577059","citation_count":175,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12529853","id":"PMC_12529853","title":"Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12529853","citation_count":141,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16721850","id":"PMC_16721850","title":"Changing distribution of norovirus genotypes and genetic analysis of recombinant GIIb among infants and children with diarrhea in Japan.","date":"2006","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/16721850","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8621453","id":"PMC_8621453","title":"Identification of p90, a prominent tyrosine-phosphorylated protein in fibroblast growth factor-stimulated cells, as 80K-H.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8621453","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15100231","id":"PMC_15100231","title":"80K-H as a new Ca2+ sensor regulating the activity of the epithelial Ca2+ channel transient receptor potential cation channel V5 (TRPV5).","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15100231","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16835903","id":"PMC_16835903","title":"Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16835903","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22337885","id":"PMC_22337885","title":"TRIM67 protein negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22337885","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15707389","id":"PMC_15707389","title":"Identification of 80K-H as a protein involved in GLUT4 vesicle trafficking.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15707389","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19801576","id":"PMC_19801576","title":"PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19801576","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18990696","id":"PMC_18990696","title":"80K-H interacts with inositol 1,4,5-trisphosphate (IP3) receptors and regulates IP3-induced calcium release activity.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18990696","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31320625","id":"PMC_31320625","title":"PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31320625","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20095989","id":"PMC_20095989","title":"Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.","date":"2010","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20095989","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34100450","id":"PMC_34100450","title":"Down-regulating Circular RNA Prkcsh suppresses the inflammatory response after spinal cord injury.","date":"2022","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/34100450","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15057895","id":"PMC_15057895","title":"Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease.","date":"2004","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/15057895","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30342075","id":"PMC_30342075","title":"A newly isolated Chinese virulent genotype GIIb porcine epidemic diarrhea virus strain: Biological characteristics, pathogenicity and immune protective effects as an inactivated vaccine candidate.","date":"2018","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/30342075","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30827401","id":"PMC_30827401","title":"Evaluation and comparison of immunogenicity and cross-protective efficacy of two inactivated cell culture-derived GIIa- and GIIb-genotype porcine epidemic diarrhea virus vaccines in suckling piglets.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30827401","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10684806","id":"PMC_10684806","title":"Vacuolar system-associated protein-60: a protein characterized from bovine granulosa and luteal cells that is associated with intracellular vesicles and related to human 80K-H and murine beta-glucosidase II.","date":"2000","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10684806","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18224332","id":"PMC_18224332","title":"Cysts of PRKCSH mutated polycystic liver disease patients lack hepatocystin but express Sec63p.","date":"2008","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18224332","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12841677","id":"PMC_12841677","title":"Elevated 80K-H protein in breast cancer: a role for FGF-1 stimulation of 80K-H.","date":"2003","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/12841677","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12750905","id":"PMC_12750905","title":"Immunolocalization of vacuolar system-associated protein-60 (VASAP-60).","date":"2003","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12750905","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17953996","id":"PMC_17953996","title":"Genotyping of GII.4 and GIIb norovirus RT-PCR amplicons by RFLP analysis.","date":"2007","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/17953996","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9821847","id":"PMC_9821847","title":"XV454, a novel nonpeptide small-molecule platelet GIIb/IIIa antagonist with comparable platelet alpha(IIb)beta3-binding kinetics to c7E3.","date":"1998","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9821847","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23644164","id":"PMC_23644164","title":"Hepatocystin/80K-H inhibits replication of hepatitis B virus through interaction with HBx protein in hepatoma cell.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23644164","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9043864","id":"PMC_9043864","title":"A 3-Mb region for the familial hemiplegic migraine locus on 19p13.1-p13.2: exclusion of PRKCSH as a candidate gene. Dutch Migraine Genetic Research Group.","date":"1996","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/9043864","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37201320","id":"PMC_37201320","title":"Recombinant human adenovirus type 5 based vaccine candidates against GIIa- and GIIb-genotype porcine epidemic diarrhea virus induce robust humoral and cellular response in mice.","date":"2023","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/37201320","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32425726","id":"PMC_32425726","title":"PRKCSH Alternative Splicing Involves in Silica-Induced Expression of Epithelial-Mesenchymal Transition Markers and Cell Proliferation.","date":"2020","source":"Dose-response : a publication of International Hormesis Society","url":"https://pubmed.ncbi.nlm.nih.gov/32425726","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16437702","id":"PMC_16437702","title":"Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.","date":"2005","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16437702","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38571496","id":"PMC_38571496","title":"Navigating PRKCSH's impact on cancer: from N-linked glycosylation to death pathway and anti-tumor immunity.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38571496","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38200153","id":"PMC_38200153","title":"PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38200153","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19308730","id":"PMC_19308730","title":"PRKCSH genetic mutation was not found in Taiwanese patients with polycystic liver disease.","date":"2009","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19308730","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40189587","id":"PMC_40189587","title":"PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40189587","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26365003","id":"PMC_26365003","title":"Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.","date":"2015","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/26365003","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31420557","id":"PMC_31420557","title":"Publisher Correction: PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31420557","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41350724","id":"PMC_41350724","title":"PRKCSH deficiency promotes an anti-tumor immune microenvironment via UPR activation and M1 macrophage polarization.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41350724","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40872827","id":"PMC_40872827","title":"Acute Febrile Illness Associated with an Emerging Dengue 4 GIIb Variant Causing Epidemic in León, Nicaragua 2022.","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/40872827","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.07.01.601633","title":"Epilepsy protein myoclonin1 interacts with inositol 1,4,5–trisphosphate (IP<sub>3</sub>) receptor and reduces Ca<sup>2+</sup>store in endoplasmic reticulum","date":"2024-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.01.601633","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22190034","id":"PMC_22190034","title":"Global landscape of HIV-human protein complexes.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22190034","citation_count":593,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33845483","id":"PMC_33845483","title":"Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33845483","citation_count":532,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12665801","id":"PMC_12665801","title":"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides.","date":"2003","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12665801","citation_count":485,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26871637","id":"PMC_26871637","title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26871637","citation_count":423,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20360068","id":"PMC_20360068","title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20360068","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9846883","id":"PMC_9846883","title":"Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs.","date":"1998","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/9846883","citation_count":344,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32838362","id":"PMC_32838362","title":"Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis.","date":"2020","source":"Med (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/32838362","citation_count":291,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18303019","id":"PMC_18303019","title":"Getting in and out from calnexin/calreticulin cycles.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18303019","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8910335","id":"PMC_8910335","title":"Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8910335","citation_count":197,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15133510","id":"PMC_15133510","title":"Mutations in SEC63 cause autosomal dominant polycystic liver disease.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15133510","citation_count":196,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32203420","id":"PMC_32203420","title":"Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32203420","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19885,"output_tokens":3960,"usd":0.059527},"stage2":{"model":"claude-opus-4-6","input_tokens":7436,"output_tokens":2957,"usd":0.166657},"total_usd":0.485419,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":31738,"output_tokens":4451,"usd":0.08099},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8181,"output_tokens":3117,"usd":0.178245}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The protein p90/80K-H (PRKCSH) was identified as the prominent tyrosine-phosphorylated protein in FGF-stimulated fibroblasts, undergoes tyrosine phosphorylation within 30 seconds of FGF treatment, and binds specifically to the GRB-2 adaptor protein, placing it in the FGF receptor signaling pathway.\",\n      \"method\": \"2D-PAGE microsequencing, Western blotting with anti-phosphotyrosine antibodies, GST-GRB2 pulldown, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and pulldown with functional pathway placement, single lab\",\n      \"pmids\": [\"8621453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The AGE-receptor component p90 was identified as identical to 80K-H (PRKCSH); immunoprecipitated OST-48 (p60) and 80K-H (p90) both exhibited AGE-specific binding, and immune IgG against recombinant 80K-H inhibited AGE-BSA binding to cell membranes dose-dependently. Both proteins were localized to rough ER membranes as well as on the plasma membrane surface of multiple cell types.\",\n      \"method\": \"N-terminal sequencing, AGE-ligand binding assay, Western blotting, immunoprecipitation, immunostaining, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study; functional inhibition assay demonstrates direct AGE binding\",\n      \"pmids\": [\"8855306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Germline loss-of-function mutations in PRKCSH (splice-site mutations predicted to disrupt the protein) were identified as a cause of autosomal dominant polycystic liver disease; the encoded protein hepatocystin contains an LDLa domain, two EF-hand domains, and a C-terminal HDEL ER-retention sequence, consistent with an ER-localized function in N-glycosylation regulation.\",\n      \"method\": \"Linkage analysis, direct sequencing, DHPLC mutation screening, haplotype segregation\",\n      \"journal\": \"Nature genetics / American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independently replicated by two separate groups (PMID 12577059 and 12529853) identifying loss-of-function PRKCSH mutations in PCLD families\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"80K-H (PRKCSH) acts as a Ca2+ sensor that directly binds Ca2+ through two EF-hand structures and regulates TRPV5 channel activity; interaction with TRPV5 was demonstrated, the EF-hand pair, acidic glutamic stretch, and HDEL sequence are critical for TRPV5 activity, and inactivation of EF-hands reduced TRPV5-mediated Ca2+ current and increased channel sensitivity to intracellular Ca2+.\",\n      \"method\": \"cDNA microarray identification, co-immunoprecipitation, co-localization, Ca2+ binding assays, EF-hand mutagenesis, electrophysiology (patch clamp)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro Ca2+ binding assay, mutagenesis of EF-hands, electrophysiological functional readout, co-IP; multiple orthogonal methods in single study\",\n      \"pmids\": [\"15100231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"80K-H (PRKCSH) interacts with PKCζ and munc18c; yeast two-hybrid and GST pulldown defined the interaction domain (C-terminal portion of 80K-H required), insulin stimulation enhanced co-immunoprecipitation 3–5-fold, and overexpression of 80K-H constructs stimulated GLUT4 translocation to the plasma membrane proportional to their ability to associate with munc18c, identifying 80K-H as a component of the PKCζ–80K-H–munc18c GLUT4 vesicle trafficking complex.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, reciprocal co-immunoprecipitation from 3T3-L1 adipocytes and L6 myotubes, GLUT4 translocation assay, glucose uptake assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by GST pulldown and reciprocal co-IP in multiple cell types; functional GLUT4 translocation readout with domain-mapping controls\",\n      \"pmids\": [\"15707389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"80K-H (PRKCSH) directly interacts with the C-terminal tail of IP3R type 1, co-immunoprecipitates with IP3R1 in cell lysates, colocalizes in COS-7 cells and hippocampal neurons, and purified recombinant 80K-H directly enhances IP3-induced Ca2+ release from cerebellar microsomes; it also regulates ATP-induced Ca2+ release in living cells.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro direct binding assay, co-immunoprecipitation, immunocytochemistry, Ca2+ release assay with purified microsomes, live-cell ATP-stimulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro reconstitution of Ca2+ release enhancement combined with co-IP and live-cell functional assay; multiple orthogonal methods\",\n      \"pmids\": [\"18990696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hepatocystin (PRKCSH) and Sec63p localize predominantly to the endoplasmic reticulum in liver cells, as shown by cell fractionation and immunofluorescence; loss of hepatocystin expression in cyst epithelium of PRKCSH mutation carriers supports a cellular-recessive (two-hit) cystogenesis mechanism.\",\n      \"method\": \"Cell fractionation, immunofluorescence, immunohistochemistry in fetal and PCLD liver tissue\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by fractionation and IHC tied to functional (disease) consequence; single lab\",\n      \"pmids\": [\"18224332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKCSH binds the C-terminal domain of TRPP2/polycystin-2, co-localizes with TRPP2 in the ER, interacts with the ER-associated degradation factor Herp, and inhibits Herp-mediated ubiquitination of TRPP2, functioning as a chaperone-like molecule that protects TRPP2 from ERAD; overexpression or depletion of PRKCSH in zebrafish caused pronephric cysts via a shared signaling pathway with TRPP2.\",\n      \"method\": \"Co-immunoprecipitation (binding to TRPP2 C-terminal domain), co-localization in ER, ubiquitination assay, zebrafish genetic epistasis (overexpression/knockdown rescue experiments)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-specific binding, in vivo ubiquitination assay, genetic epistasis in zebrafish, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19801576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM67 interacts with 80K-H (PRKCSH) and promotes its proteasomal degradation; ectopic TRIM67 expression degrades endogenous 80K-H, attenuates cell proliferation, and enhances neuritogenesis in N1E-115 cells; knockdown of 80K-H phenocopied TRIM67 overexpression, indicating that TRIM67 negatively regulates Ras signaling via 80K-H degradation.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, knockdown experiments, morphological/proliferation assays in neuroblastoma cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP confirmed interaction, loss-of-function phenocopy validates pathway placement; single lab\",\n      \"pmids\": [\"22337885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocystin (PRKCSH) physically interacts with HBV HBx protein via the mannose 6-phosphate receptor homology domain of hepatocystin (aa 419–525) binding to the HBx C-terminus (aa 110–154); hepatocystin overexpression accelerates HBx degradation through a ubiquitin-independent proteasome pathway, thereby inhibiting HBV DNA replication and HBs antigen expression.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, immunocytochemistry, domain mapping with deletion mutants, proteasome/translation inhibitor assays, HBV replication assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping plus functional proteasomal degradation assay and HBV replication readout; single lab\",\n      \"pmids\": [\"23644164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRKCSH functions as a regulator of selective IRE1α UPR branch activation: PRKCSH boosts ER stress-induced autophosphorylation and oligomerization of IRE1α through direct mutual interaction, promoting expression of XBP1-target tumor-promoting factors and conferring tumor cell resistance to ER stress.\",\n      \"method\": \"Co-immunoprecipitation, IRE1α autophosphorylation and oligomerization assays, XBP1 splicing reporter, knockdown/overexpression in cancer cells, correlation with XBP1 target gene expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, biochemical IRE1α activation assays, functional downstream readouts; published in high-impact journal with correction notice confirming study\",\n      \"pmids\": [\"31320625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCSH interacts with IGF1R, extends its protein half-life, and thereby boosts IGF1R activation in lung cancer cells; this PRKCSH–IGF1R axis impairs caspase-8 activation and increases Mcl-1 expression, leading to resistance to TNFSF-mediated apoptosis; PRKCSH deficiency augmented NK cell antitumor activity in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assay, caspase activation assays, Mcl-1 Western blotting, tumor xenograft in IL-2Rg-deficient NOD/SCID mice\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of endogenous proteins, half-life assay, in vivo xenograft; single lab\",\n      \"pmids\": [\"38200153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCSH inhibition reduces p53 ubiquitination and degradation after ionizing radiation by activating the ER stress IRE1α/XBP1s pathway, thereby enhancing DNA repair and contributing to radioresistance in colorectal cancer cells.\",\n      \"method\": \"PRKCSH knockdown, clonogenic survival assay, apoptosis assay, p53 ubiquitination assay, IRE1α/XBP1s pathway activation analysis, patient-derived organoid models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic p53 ubiquitination assay linked to IRE1α/XBP1s pathway, supported by organoid and patient data; single lab\",\n      \"pmids\": [\"40189587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCSH interacts with myoclonin1 (EFHC1 gene product) at choroid plexus and ependymal cells; as 80K-H/PRKCSH also interacts with IP3R1, the myoclonin1–PRKCSH–IP3R1 complex modulates ER Ca2+ homeostasis, with PRKCSH acting as an intermediary linking myoclonin1 to IP3R-mediated Ca2+ release regulation.\",\n      \"method\": \"Co-expression analysis, protein–protein interaction assay (binding), ER Ca2+ measurement in Efhc1-deficient mouse cells, IP3-induced Ca2+ release assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single co-IP/interaction assay for the PRKCSH–myoclonin1 link; PRKCSH–IP3R interaction previously established\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601633\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRKCSH (80K-H/hepatocystin) is an ER-resident regulatory protein that functions as the beta (non-catalytic) subunit of glucosidase II to control N-glycoprotein processing; it acts as a Ca2+-sensing chaperone-like molecule that (via its EF-hand domains) directly modulates IP3R1- and TRPV5-mediated Ca2+ release, protects TRPP2 from Herp-mediated ERAD by inhibiting its ubiquitination, selectively boosts IRE1α autophosphorylation and oligomerization to promote the IRE1α/XBP1s branch of the UPR, interacts with IGF1R to extend its half-life and drive TNFSF resistance, participates in insulin-triggered PKCζ–80K-H–munc18c complex formation to facilitate GLUT4 vesicle trafficking, and is subject to TRIM67-mediated proteasomal degradation that attenuates Ras signaling and promotes neuritogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Glucosidase II is a two-subunit enzyme; the beta subunit (encoded by PRKCSH, then called 80K-H) is a non-catalytic, HDEL-containing subunit tightly associated with the catalytic alpha subunit. The beta subunit contains a C-terminal HDEL ER-retention signal and is responsible for ER localization of the enzyme complex.\",\n      \"method\": \"Biochemical purification of glucosidase II from rat liver, peptide sequencing, cDNA identification, and yeast gene disruption experiments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted enzyme complex, subunit sequencing, functional yeast KO, foundational paper with >197 citations\",\n      \"pmids\": [\"8910335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"80K-H (PRKCSH protein) was identified as a tyrosine-phosphorylated substrate (p90) in FGF-stimulated fibroblasts and was found to bind specifically to the SH2/SH3 adaptor protein GRB-2, placing 80K-H in the FGF receptor signaling pathway.\",\n      \"method\": \"2D-PAGE microsequencing, anti-phosphotyrosine immunoprecipitation, GST-GRB2 pulldown, Western blotting\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and pulldown, single lab\",\n      \"pmids\": [\"8621453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The AGE-receptor component p90 is identical to 80K-H (PRKCSH protein); OST-48 (p60) and 80K-H (p90) together mediate AGE binding on cell surfaces. Immunoprecipitated OST-48 from rough ER fractions exhibited AGE binding, and immune IgG to recombinant 80K-H inhibited AGE-BSA binding to cell membranes.\",\n      \"method\": \"N-terminal sequencing, AGE-ligand binding assays, Western blotting, immunoprecipitation, flow cytometry, immunostaining, antibody inhibition assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study; single lab\",\n      \"pmids\": [\"8855306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Germline loss-of-function mutations in PRKCSH (splice-site mutations) cause autosomal dominant polycystic liver disease (PCLD), establishing PRKCSH as a disease gene. The protein, named hepatocystin, is predicted to localize to the ER.\",\n      \"method\": \"Genetic linkage mapping, mutation analysis by sequencing, disease segregation analysis in four Dutch families\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via disease linkage, replicated across multiple families, independently confirmed by second lab\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PRKCSH encodes the noncatalytic beta-subunit of glucosidase II, a protein highly conserved across tissues, containing an LDLa domain, two EF-hand domains, and a C-terminal HDEL ER-retention sequence, with proposed roles in N-glycosylation regulation and FGF receptor signal transduction.\",\n      \"method\": \"Sequence analysis, DHPLC heteroduplex analysis, direct sequencing for mutation detection, domain annotation\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and sequence-based functional annotation; independently corroborated by Drenth et al.\",\n      \"pmids\": [\"12529853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"80K-H (PRKCSH protein) acts as a Ca2+ sensor that directly interacts with and regulates the epithelial Ca2+ channel TRPV5. Ca2+ binding via two EF-hand domains in 80K-H modulates TRPV5 channel activity; inactivation of the EF-hands abolished Ca2+ binding and altered TRPV5-mediated Ca2+ current and sensitivity to intracellular Ca2+. The HDEL and acidic glutamic stretch domains are also required for full TRPV5 regulation. Both proteins co-localize in kidney.\",\n      \"method\": \"cDNA microarray identification, co-immunoprecipitation, co-localization (immunofluorescence), Ca2+-binding assay, electrophysiology with domain mutants\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct Ca2+-binding assay, mutagenesis of EF-hands, electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"15100231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"80K-H (PRKCSH protein) interacts with PKCzeta and munc18c in an insulin-dependent manner, forming a trimeric complex (PKCzeta–80K-H–munc18c) that promotes GLUT4 vesicle translocation to the plasma membrane. Overexpression of 80K-H mimicked insulin's effect on glucose uptake and GLUT4 translocation, proportional to its ability to associate with munc18c.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, endogenous co-immunoprecipitation from adipocytes and myotubes, glucose uptake assay, GLUT4 translocation assay\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP in multiple cell types, functional overexpression assay, multiple orthogonal methods\",\n      \"pmids\": [\"15707389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"80K-H (PRKCSH protein) directly interacts with the C-terminal tail of IP3 receptor type 1 (IP3R1), co-localizes with IP3R1 in COS-7 cells and hippocampal neurons, and directly enhances IP3-induced Ca2+ release from ER microsomes. 80K-H also regulates ATP-induced Ca2+ release in living cells.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro direct binding assay, co-immunoprecipitation, immunocytochemistry/immunohistochemistry, Ca2+ release assay with purified recombinant 80K-H\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstituted Ca2+ release assay with purified protein plus co-IP and co-localization\",\n      \"pmids\": [\"18990696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hepatocystin (PRKCSH protein) localizes predominantly to the ER in liver cells (both hepatocytes and bile duct epithelia). In PCLD patients with PRKCSH mutations, cyst epithelium lacks hepatocystin expression (consistent with a two-hit/loss-of-function mechanism), while Sec63p is still expressed in all cysts. Hepatocystin and Sec63p do not interact with each other.\",\n      \"method\": \"Cell fractionation, immunofluorescence, immunohistochemistry in fetal and adult liver and PCLD cyst tissue\",\n      \"journal\": \"Histochemistry and Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional inference; single lab\",\n      \"pmids\": [\"18224332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKCSH (hepatocystin) functions as a chaperone-like molecule that binds the C-terminal domain of TRPP2/polycystin-2 within the ER and protects TRPP2 from HERP-mediated ubiquitination and ER-associated degradation (ERAD). PRKCSH interacts with Herp and inhibits Herp-mediated ubiquitination of TRPP2. Over-expression or depletion of PRKCSH in zebrafish embryos phenocopies TRPP2 perturbation (pronephric cysts, body curvature, situs inversus), indicating a shared signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, zebrafish overexpression/morpholino knockdown, ubiquitination assay, genetic epistasis in zebrafish\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, ubiquitination assay, in vivo genetic epistasis in zebrafish with multiple orthogonal methods\",\n      \"pmids\": [\"19801576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM67 E3 ubiquitin ligase interacts with 80K-H (PRKCSH protein) and promotes its proteasomal degradation. Ectopic TRIM67 expression reduces endogenous 80K-H levels, attenuates cell proliferation, and enhances neuritogenesis in N1E-115 neuroblastoma cells; 80K-H knockdown phenocopies TRIM67 overexpression, indicating 80K-H is a downstream effector of TRIM67 in Ras-mediated signaling and neural differentiation.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, cell proliferation assay, neuritogenesis assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional knockdown/OE with phenotypic readout; single lab\",\n      \"pmids\": [\"22337885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocystin (PRKCSH protein) interacts with HBx protein of hepatitis B virus via its mannose 6-phosphate receptor homology domain (aa 419–525) binding to HBx C-terminus (aa 110–154). Hepatocystin overexpression accelerates HBx degradation via a ubiquitin-independent proteasome pathway, inhibiting HBV DNA replication and HBs antigen expression.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, Western blot, immunocytochemistry, domain mapping, proteasome/translation inhibitor assays, HBV replication assay\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, domain mapping, functional assay; single lab\",\n      \"pmids\": [\"23644164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRKCSH functions as a selective regulator of the IRE1α branch of the unfolded protein response (UPR). PRKCSH directly interacts with IRE1α and boosts its ER stress-mediated autophosphorylation and oligomerization, leading to selective activation of IRE1α/XBP1 signaling. This promotes expression of tumor-promoting factors and confers tumor cell resistance to ER stress.\",\n      \"method\": \"Co-immunoprecipitation, autophosphorylation assay, oligomerization assay, PRKCSH knockdown/overexpression, XBP1 target gene expression analysis, in vivo tumor models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction + functional phosphorylation/oligomerization assays + in vivo validation; multiple methods\",\n      \"pmids\": [\"31320625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCSH interacts with IGF1R and extends its protein half-life (stabilizes it), thereby boosting IGF1R oncogenic signaling in lung cancer cells. The PRKCSH-IGF1R axis impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, promoting TNFSF resistance. PRKCSH deficiency augments NK cell-mediated antitumor killing in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assay, caspase activation assay, Mcl-1 expression analysis, siRNA knockdown, tumor xenograft model with NK cells\",\n      \"journal\": \"Experimental & Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus protein stability assay and in vivo xenograft; single lab\",\n      \"pmids\": [\"38200153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCSH inhibition in colorectal cancer cells sensitizes them to ionizing radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduces p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation, impairing DNA repair and thus reducing radioresistance.\",\n      \"method\": \"PRKCSH knockdown, clonogenic survival assay, apoptosis assay, DNA damage repair assay, p53 ubiquitination assay, IRE1α/XBP1s pathway analysis, patient-derived organoids, tumor xenograft\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement with multiple assays; single lab\",\n      \"pmids\": [\"40189587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCSH deficiency in lung adenocarcinoma cells leads to exaggerated IRE1α activation under ER stress (increased XBP1s and p-JNK), suppresses IL-6 and IL-8 secretion, promotes M1 macrophage polarization (increased CD86+ macrophages), and enhances susceptibility to ER stress-induced apoptosis and ferroptosis while impairing autophagy.\",\n      \"method\": \"CRISPR/Cas9 KO, cytokine profiling, macrophage co-culture, flow cytometry, zebrafish xenograft, clinical pleural effusion sample analysis\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with multiple functional readouts and in vivo zebrafish validation; single lab\",\n      \"pmids\": [\"41350724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myoclonin1 (EFHC1 protein) interacts with PRKCSH (80K-H), which itself interacts with IP3R1, placing PRKCSH at the intersection of a myoclonin1–PRKCSH–IP3R complex that modulates ER Ca2+ homeostasis and IP3-induced Ca2+ release.\",\n      \"method\": \"Co-immunoprecipitation, Ca2+ measurement in Efhc1-deficient mouse cells, IP3-induced Ca2+ release assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-IP interaction; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601633\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRKCSH encodes hepatocystin/80K-H, the non-catalytic beta subunit of ER glucosidase II that retains the enzyme complex in the ER via its HDEL signal; it acts as a Ca2+-sensing chaperone-like regulator that protects client glycoproteins (e.g., TRPP2) from HERP-mediated ERAD, modulates IP3R1-dependent and TRPV5-dependent Ca2+ signaling via EF-hand domains, promotes GLUT4 vesicle trafficking through a PKCzeta–80K-H–munc18c complex, and selectively boosts IRE1α autophosphorylation and oligomerization to activate the XBP1 branch of the UPR, while loss-of-function germline mutations cause autosomal dominant polycystic liver disease through a two-hit cystogenesis mechanism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRKCSH (80K-H/hepatocystin) is an ER-resident, Ca2+-sensing glycoprotein that participates in protein quality control, Ca2+ signaling, and stress-response pathways. It binds Ca2+ through two EF-hand domains and directly modulates IP3R1-mediated and TRPV5-mediated Ca2+ release, while also functioning as a chaperone-like molecule that protects TRPP2/polycystin-2 from Herp-mediated ER-associated degradation by inhibiting its ubiquitination [PMID:15100231, PMID:18990696, PMID:19801576]. PRKCSH selectively enhances the IRE1α/XBP1s branch of the unfolded protein response by promoting IRE1α autophosphorylation and oligomerization, and it stabilizes IGF1R to confer resistance to TNFSF-mediated apoptosis in cancer cells [PMID:31320625, PMID:38200153]. Germline loss-of-function mutations in PRKCSH cause autosomal dominant polycystic liver disease [PMID:12577059, PMID:12529853].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that 80K-H is an early FGF-signaling participant and AGE-binding protein placed it at the intersection of growth factor and glycation pathways, though its core ER function was not yet recognized.\",\n      \"evidence\": \"Tyrosine phosphorylation kinetics and GRB2 pulldown in FGF-stimulated fibroblasts; AGE-ligand binding and inhibition assays with anti-80K-H antibodies\",\n      \"pmids\": [\"8621453\", \"8855306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GRB2 interaction not independently replicated\", \"AGE-binding function not connected to downstream signaling pathway\", \"Relationship to ER glycoprotein processing unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of germline PRKCSH loss-of-function mutations as the cause of autosomal dominant polycystic liver disease established the gene's essential role in hepatic epithelial homeostasis and pointed to ER-resident glycoprotein processing as the disease-relevant function.\",\n      \"evidence\": \"Linkage analysis and mutation screening in independent PCLD families by two groups\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking loss of hepatocystin to cyst formation not defined\", \"Two-hit vs. haploinsufficiency not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that PRKCSH directly binds Ca2+ via its EF-hand domains and regulates TRPV5 channel activity established it as a bona fide Ca2+ sensor coupling ER luminal Ca2+ to ion channel function.\",\n      \"evidence\": \"Ca2+ binding assays, EF-hand mutagenesis, patch-clamp electrophysiology, and co-immunoprecipitation with TRPV5\",\n      \"pmids\": [\"15100231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of EF-hand–TRPV5 interaction unknown\", \"In vivo relevance to renal Ca2+ handling not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying 80K-H as part of a PKCζ–80K-H–munc18c complex that promotes insulin-stimulated GLUT4 translocation revealed a metabolic signaling role distinct from its ER quality-control functions.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reciprocal co-IP in adipocytes and myotubes, GLUT4 translocation assay\",\n      \"pmids\": [\"15707389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 80K-H acts at the plasma membrane or ER in this context unclear\", \"Phosphorylation site mediating insulin-dependent complex assembly not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that purified PRKCSH directly enhances IP3-induced Ca2+ release from microsomes and colocalizes with IP3R1 in neurons provided reconstituted biochemical proof of its Ca2+-regulatory mechanism, extending the Ca2+-sensor paradigm from TRPV5 to IP3 receptors.\",\n      \"evidence\": \"In vitro Ca2+ release assay with purified microsomes, yeast two-hybrid, co-IP, immunocytochemistry in hippocampal neurons\",\n      \"pmids\": [\"18990696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and affinity of PRKCSH–IP3R1 complex not determined\", \"Whether both EF-hand and HDEL domains are required for IP3R1 modulation not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cell fractionation confirming ER-predominant localization of hepatocystin in liver, together with loss of expression in cyst epithelium, supported a cellular-recessive (two-hit) mechanism for PCLD cystogenesis.\",\n      \"evidence\": \"Cell fractionation and immunohistochemistry of PCLD liver tissue\",\n      \"pmids\": [\"18224332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Second somatic hit not molecularly characterized in most cysts\", \"Role of hepatocystin loss in downstream proliferative signaling not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that PRKCSH protects TRPP2 from Herp-mediated ERAD by inhibiting its ubiquitination, and that genetic perturbation in zebrafish caused cysts epistatic with TRPP2, mechanistically linked PRKCSH to the polycystin pathway and explained the cystic disease phenotype.\",\n      \"evidence\": \"Co-IP with TRPP2 C-terminus, ubiquitination assays, zebrafish overexpression/knockdown epistasis\",\n      \"pmids\": [\"19801576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRKCSH chaperone function extends to other ERAD substrates not tested\", \"Structural basis of Herp inhibition unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of TRIM67 as an E3 ligase that targets 80K-H for proteasomal degradation, thereby attenuating Ras signaling and promoting neuritogenesis, revealed that PRKCSH levels are actively regulated to control cell fate decisions.\",\n      \"evidence\": \"Co-IP, TRIM67 overexpression/knockdown, 80K-H protein levels, proliferation and neurite outgrowth assays in neuroblastoma cells\",\n      \"pmids\": [\"22337885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of 80K-H by TRIM67 not demonstrated in vitro\", \"Physiological relevance in primary neurons not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that PRKCSH selectively promotes IRE1α autophosphorylation and oligomerization to activate the XBP1s branch of the UPR established a direct role in ER stress signaling beyond its known quality-control and Ca2+-sensing activities.\",\n      \"evidence\": \"Reciprocal co-IP, IRE1α phosphorylation/oligomerization assays, XBP1 splicing reporter, knockdown/overexpression in cancer cells\",\n      \"pmids\": [\"31320625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRKCSH binds IRE1α luminal or cytoplasmic domain not resolved\", \"Selectivity mechanism sparing PERK and ATF6 branches not elucidated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Finding that PRKCSH stabilizes IGF1R and thereby suppresses caspase-8 activation and TNFSF-induced apoptosis extended the oncogenic relevance of PRKCSH from UPR modulation to receptor tyrosine kinase stability and immune evasion.\",\n      \"evidence\": \"Co-IP, IGF1R half-life assay, caspase activation assays, NK cell xenograft model\",\n      \"pmids\": [\"38200153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IGF1R stabilization (glycosylation-dependent vs. direct) not distinguished\", \"Single xenograft model; not validated in immunocompetent system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking PRKCSH to p53 stabilization after ionizing radiation via the IRE1α/XBP1s axis extended the UPR-modulatory role to DNA damage response and radioresistance, connecting two previously separate PRKCSH functions.\",\n      \"evidence\": \"PRKCSH knockdown, p53 ubiquitination assay, clonogenic survival, patient-derived organoid models\",\n      \"pmids\": [\"40189587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PRKCSH affects p53 directly or solely through XBP1s transcriptional targets not resolved\", \"Not confirmed in non-colorectal cancer models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural understanding of how PRKCSH simultaneously serves as glucosidase II β-subunit, Ca2+ sensor, IRE1α co-activator, and protein stabilizer — and how these functions are coordinated or compartmentalized — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of PRKCSH in complex with any binding partner\", \"Relative contributions of glucosidase II-dependent vs. -independent functions to cystogenesis not dissected\", \"Tissue-specific regulation of PRKCSH protein levels and post-translational modifications poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 7, 10]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [\n      \"glucosidase II (α/β)\",\n      \"PKCζ–80K-H–munc18c\"\n    ],\n    \"partners\": [\n      \"TRPV5\",\n      \"ITPR1\",\n      \"PKD2\",\n      \"IRE1α\",\n      \"PRKCZ\",\n      \"MUNC18C\",\n      \"IGF1R\",\n      \"TRIM67\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRKCSH encodes the non-catalytic beta subunit of ER glucosidase II, functioning as an ER-resident regulatory and chaperone-like glycoprotein that integrates N-glycan processing with Ca²⁺ signaling, protein quality control, and the unfolded protein response. Its C-terminal HDEL signal retains the glucosidase II holoenzyme in the ER, while its EF-hand domains sense Ca²⁺ to regulate ion channels including TRPV5 and IP3R1, and it protects client glycoproteins such as TRPP2 from HERP-mediated ERAD [PMID:8910335, PMID:15100231, PMID:18990696, PMID:19801576]. PRKCSH selectively promotes IRE1α autophosphorylation and oligomerization, activating the XBP1 branch of the UPR; in cancer contexts this confers ER-stress resistance and modulates tumor immune evasion via cytokine and apoptotic pathways [PMID:31320625, PMID:40189587, PMID:41350724]. Germline loss-of-function mutations in PRKCSH cause autosomal dominant polycystic liver disease through a two-hit cystogenesis mechanism [PMID:12577059, PMID:12529853].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The identity of PRKCSH as the non-catalytic beta subunit of glucosidase II established its core enzymatic partnership and ER-retention mechanism, answering how glucosidase II is localized and assembled in the ER.\",\n      \"evidence\": \"Biochemical purification from rat liver, peptide sequencing, cDNA cloning, and yeast gene disruption\",\n      \"pmids\": [\"8910335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic contribution of the beta subunit to trimming activity not defined\", \"Structural basis of alpha-beta interaction unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Parallel findings placed 80K-H as a signaling-competent molecule — a tyrosine-phosphorylated FGF-receptor substrate binding GRB2 and a component of AGE receptor complexes — suggesting roles beyond glucosidase II scaffolding.\",\n      \"evidence\": \"Phosphotyrosine immunoprecipitation, GST-GRB2 pulldown (FGF signaling); AGE-ligand binding, antibody inhibition assays (AGE receptor)\",\n      \"pmids\": [\"8621453\", \"8855306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FGF/GRB2 interaction not confirmed with reciprocal endogenous IP\", \"Physiological relevance of AGE binding not established in vivo\", \"Relationship between ER-resident function and cell-surface signaling roles unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of PRKCSH germline mutations in polycystic liver disease families established it as a disease gene and implied that loss of hepatocystin's ER functions drives cystogenesis.\",\n      \"evidence\": \"Linkage mapping and mutation analysis across multiple Dutch families, independently confirmed by a second group\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking glucosidase II beta loss to cholangiocyte cyst formation not defined\", \"Nature of second hit not characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that PRKCSH's EF-hand domains sense Ca²⁺ and directly regulate the TRPV5 channel established a Ca²⁺-sensor function independent of its glucosidase II role.\",\n      \"evidence\": \"Co-IP, Ca²⁺-binding assays with EF-hand mutants, electrophysiology of TRPV5 currents\",\n      \"pmids\": [\"15100231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ca²⁺ sensing and glucosidase II scaffolding are mutually exclusive activities is unknown\", \"In vivo renal Ca²⁺ phenotype in PRKCSH-deficient animals not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of a PKCζ–80K-H–munc18c trimeric complex that promotes GLUT4 translocation revealed PRKCSH as an adaptor in insulin-stimulated glucose uptake.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP from adipocytes and myotubes, GLUT4 translocation and glucose uptake assays\",\n      \"pmids\": [\"15707389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of trimeric complex assembly unknown\", \"Relevance to PCLD pathogenesis not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Direct enhancement of IP3-induced Ca²⁺ release by purified 80K-H binding to IP3R1 established PRKCSH as a positive modulator of ER Ca²⁺ store mobilization, and ER localization of hepatocystin in cholangiocytes with loss in PCLD cysts supported a two-hit cystogenesis model.\",\n      \"evidence\": \"In vitro reconstituted Ca²⁺ release assay with purified protein, co-IP, immunohistochemistry of PCLD cyst tissue\",\n      \"pmids\": [\"18990696\", \"18224332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IP3R1 modulation is Ca²⁺-EF-hand-dependent not tested\", \"Two-hit mechanism not genetically proven at the somatic level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"PRKCSH was shown to protect TRPP2/polycystin-2 from HERP-mediated ubiquitination and ERAD, and zebrafish epistasis phenocopied polycystin-2 perturbation, providing a mechanistic link between PRKCSH loss and cystic disease.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, zebrafish morpholino/overexpression with pronephric cyst and laterality phenotypes\",\n      \"pmids\": [\"19801576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether glucosidase II trimming activity is required for the TRPP2-protective function is unknown\", \"Mammalian in vivo confirmation lacking\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of TRIM67-mediated proteasomal degradation of 80K-H, with phenotypic consequences for neuritogenesis, revealed upstream regulation of PRKCSH protein levels in neural differentiation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, TRIM67 overexpression, proliferation and neuritogenesis assays in neuroblastoma cells\",\n      \"pmids\": [\"22337885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin site(s) on 80K-H not mapped\", \"In vivo neuronal phenotype of PRKCSH loss not examined\", \"Single cell line (N1E-115)\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PRKCSH was established as a selective activator of the IRE1α/XBP1 branch of the UPR through direct interaction with IRE1α and promotion of its autophosphorylation and oligomerization, linking PRKCSH to ER-stress signaling and tumor biology.\",\n      \"evidence\": \"Co-IP, autophosphorylation and oligomerization assays, PRKCSH knockdown/overexpression, XBP1 target gene profiling, in vivo tumor models\",\n      \"pmids\": [\"31320625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRE1α interaction is glycan-dependent or direct protein–protein is unclear\", \"Relationship between glucosidase II activity and UPR regulation not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"PRKCSH stabilizes IGF1R protein to boost oncogenic survival signaling, impairing caspase-8 activation and conferring TNFSF resistance, and its loss enhances NK cell-mediated tumor killing, expanding its tumor-promoting functions beyond UPR modulation.\",\n      \"evidence\": \"Co-IP, protein half-life assay, caspase activation assays, xenograft model with NK cells\",\n      \"pmids\": [\"38200153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IGF1R stabilization is glycan-processing-dependent not tested\", \"Single cancer type (lung)\", \"NK cell killing mechanism not fully dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In colorectal and lung cancer cells, PRKCSH inhibition was shown to sensitize tumors to ionizing radiation and ferroptosis through exaggerated IRE1α activation, p53 stabilization, and altered macrophage polarization, consolidating PRKCSH as a multifaceted regulator of tumor-immune and stress-response crosstalk.\",\n      \"evidence\": \"PRKCSH knockdown and CRISPR KO, clonogenic survival, apoptosis, DNA repair assays, cytokine profiling, macrophage co-culture, patient-derived organoids, xenograft models\",\n      \"pmids\": [\"40189587\", \"41350724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic window for PRKCSH inhibition not defined\", \"Contribution of glucosidase II catalytic activity versus non-catalytic functions in these phenotypes not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is whether the diverse functions of PRKCSH — glucosidase II scaffolding, Ca²⁺ sensing, ERAD protection, IRE1α activation, and receptor stabilization — represent independent activities of distinct domains or are mechanistically coupled through its glycan-processing role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the full glucosidase II complex with client substrates\", \"Domain-specific separation-of-function mutants for glucosidase II versus signaling roles not systematically generated\", \"Conditional knockout mouse model to separate hepatic versus extrahepatic functions not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 12]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6, 7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 13, 14, 15]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [\n      \"Glucosidase II (alpha-beta heterodimer)\",\n      \"PKCζ–80K-H–munc18c complex\"\n    ],\n    \"partners\": [\n      \"GIIα (GANAB)\",\n      \"TRPV5\",\n      \"ITPR1\",\n      \"PKD2\",\n      \"PRKCZ\",\n      \"MUNC18C (STXBP3)\",\n      \"IRE1α (ERN1)\",\n      \"IGF1R\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}