{"gene":"PRKCSH","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1996,"finding":"The AGE receptor component p90 (80K-H/PRKCSH) was identified as identical to the previously described 80K-H protein kinase C substrate. Immunostaining and flow cytometry demonstrated surface expression on multiple cell types, and immune IgG raised to recombinant 80K-H inhibited AGE-BSA binding to cell membranes in a dose-dependent manner, establishing 80K-H as a functional AGE-binding protein.","method":"Protein sequencing, immunoprecipitation, AGE-ligand binding assay, flow cytometry, antibody inhibition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation and functional inhibition by antibody in a single lab, multiple orthogonal methods","pmids":["8855306"],"is_preprint":false},{"year":1996,"finding":"80K-H (PRKCSH) was identified as the tyrosine-phosphorylated protein p90 in FGF-stimulated fibroblasts. 80K-H was specifically tyrosine-phosphorylated within 30 seconds of FGF (but not other growth factors) stimulation and was found to bind specifically to GRB-2-GST fusion protein, placing it downstream of FGF receptor in a signaling pathway.","method":"2D-PAGE microsequencing, Western blot with anti-phosphotyrosine antibody, immunoprecipitation, GST pulldown with GRB-2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown, single lab with multiple orthogonal methods","pmids":["8621453"],"is_preprint":false},{"year":2003,"finding":"Germline loss-of-function mutations in PRKCSH (splice-acceptor and splice-donor site mutations) were identified as the genetic cause of autosomal dominant polycystic liver disease (PCLD), establishing PRKCSH as necessary for normal biliary epithelial homeostasis.","method":"Genetic linkage mapping, direct sequencing of PRKCSH in PCLD families, segregation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently across two simultaneous studies (PMIDs 12577059 and 12529853) using sequencing and segregation analysis in multiple families","pmids":["12577059","12529853"],"is_preprint":false},{"year":2000,"finding":"Bovine ortholog VASAP-60 (80K-H/PRKCSH) was localized predominantly to the endoplasmic reticulum (co-localizing with calnexin) and partially to endocytic compartments, and was found in a membrane fraction unglycosylated. Immunoprecipitation demonstrated interaction with 116-, 48.5-, and 26.5-kDa proteins, suggesting a role in intracellular transport events.","method":"Cell fractionation, immunocytochemistry with ER marker co-localization, endoglycosidase H treatment, immunoprecipitation of metabolically labeled cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional context, single lab, multiple orthogonal methods","pmids":["10684806"],"is_preprint":false},{"year":2003,"finding":"VASAP-60/80K-H (PRKCSH) was localized to the perinuclear ER (co-localizing with calnexin) and partially to endocytic/vacuolar compartments in bovine tissues and cell lines. A 58-kDa proteolytically processed form was identified, and the protein's anomalous migration (88 kDa observed vs. 60.1 kDa predicted) was attributed to its glutamic/aspartic acid-rich central region.","method":"Immunocytochemistry with calnexin co-localization, immunohistochemistry, immunoblotting, SDS-PAGE analysis of recombinant domain fragments","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization with functional structural insight, single lab, orthogonal methods","pmids":["12750905"],"is_preprint":false},{"year":2004,"finding":"80K-H (PRKCSH) was identified as a Ca2+ sensor that directly interacts with and regulates the epithelial Ca2+ channel TRPV5. 80K-H directly bound Ca2+ through its two EF-hand structures; inactivation of EF-hands abolished Ca2+ binding and reduced TRPV5-mediated Ca2+ current while increasing TRPV5 sensitivity to intracellular Ca2+, accelerating feedback inhibition. The highly acidic glutamic stretch and the HDEL sequence were also identified as critical determinants for TRPV5 activity. Neither EF-hand inactivation nor other 80K-H mutations altered TRPV5 plasma membrane localization or 80K-H-TRPV5 association.","method":"cDNA microarray identification, co-immunoprecipitation, co-localization, Ca2+ binding assay with EF-hand mutants, electrophysiology with 80K-H mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro Ca2+ binding assay with mutagenesis, electrophysiological functional validation, multiple orthogonal methods in single rigorous study","pmids":["15100231"],"is_preprint":false},{"year":2005,"finding":"80K-H (PRKCSH) was identified as an interactor with PKCzeta via yeast two-hybrid screening, confirmed by GST pulldown showing the N-terminal portion of 80K-H was not required for this interaction. Endogenous co-immunoprecipitation confirmed a physiological PKCzeta-80K-H interaction that was enhanced 3-5-fold by insulin. 80K-H also co-immunoprecipitated with munc18c, forming a PKCzeta-80K-H-munc18c complex upon insulin stimulation. Overexpression of 80K-H constructs stimulated glucose uptake and GLUT4 translocation proportional to their ability to associate with munc18c.","method":"Yeast two-hybrid, GST pulldown, endogenous co-immunoprecipitation, GLUT4 translocation assay, glucose uptake assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmed in multiple cell types, GST pulldown with domain mapping, functional overexpression assay, multiple orthogonal methods","pmids":["15707389"],"is_preprint":false},{"year":2008,"finding":"80K-H (PRKCSH) was identified as a novel interactor with the C-terminal tail of IP3R type 1 via yeast two-hybrid screening. Direct in vitro interaction was confirmed by pull-down assay. 80K-H co-immunoprecipitated with IP3R1 in cell lysates and co-localized with IP3R1 in COS-7 cells and hippocampal neurons. Purified recombinant 80K-H directly enhanced IP3-induced Ca2+ release activity in mouse cerebellar microsomes, and 80K-H regulated ATP-induced Ca2+ release in living cells.","method":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, immunocytochemistry, Ca2+ release assay with cerebellar microsomes, live-cell Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of Ca2+ release enhancement with purified recombinant protein, validated by multiple orthogonal methods including co-IP and live-cell assays","pmids":["18990696"],"is_preprint":false},{"year":2008,"finding":"Hepatocystin (PRKCSH) and Sec63p were both localized predominantly to the endoplasmic reticulum by cell fractionation, immunofluorescence, and immunohistochemistry. Cysts from PRKCSH mutation carriers specifically lacked hepatocystin expression, while all cysts regardless of mutation status expressed Sec63p, supporting a cellular recessive (two-hit) mechanism for cystogenesis in PRKCSH-associated PCLD.","method":"Cell fractionation, immunofluorescence, immunohistochemistry of PCLD and normal liver tissue","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization with functional consequence (loss of hepatocystin in cysts), multiple orthogonal methods, single lab","pmids":["18224332"],"is_preprint":false},{"year":2010,"finding":"PRKCSH (hepatocystin) was shown to bind the C-terminal domain of TRPP2/polycystin-2 and co-localize with TRPP2 within the ER. PRKCSH interacts with Herp and inhibits Herp-mediated ubiquitination of TRPP2, thereby functioning as a chaperone-like molecule that protects TRPP2 against ER-associated degradation (ERAD). Over-expression or depletion of PRKCSH in zebrafish embryos caused pronephric cysts, and TRPP2 overexpression could rescue PRKCSH depletion phenotypes (and vice versa), establishing epistasis.","method":"Co-immunoprecipitation, co-localization, ubiquitination assay, zebrafish knockdown/overexpression with epistasis rescue experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo epistasis rescue, multiple orthogonal methods in single study","pmids":["19801576"],"is_preprint":false},{"year":2012,"finding":"TRIM67 was found to interact with 80K-H (PRKCSH) and induce its proteasomal degradation. Ectopic TRIM67 expression degraded endogenous 80K-H, attenuated cell proliferation, and enhanced neuritogenesis in N1E-115 neuroblastoma cells. Knockdown of 80K-H alone phenocopied TRIM67 overexpression, and these changes were linked to attenuation of Ras-mediated signaling.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, cell proliferation assay, neuritogenesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function phenocopy with defined cellular readouts, single lab","pmids":["22337885"],"is_preprint":false},{"year":2013,"finding":"Hepatocystin/PRKCSH directly interacts with HBV X protein (HBx): the HBx C-terminus (aa 110-154) binds the mannose 6-phosphate receptor homology domain (aa 419-525) of hepatocystin. Hepatocystin overexpression accelerated HBx degradation via a ubiquitin-independent proteasomal pathway, significantly inhibited HBV DNA replication and HBs antigen expression in a manner dependent on the HBx-binding domain of hepatocystin.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, immunocytochemistry, domain mapping with deletion mutants, proteasome inhibitor studies, HBV replication assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping by deletion mutants, functional HBV replication assay, multiple orthogonal methods in single rigorous study","pmids":["23644164"],"is_preprint":false},{"year":2019,"finding":"PRKCSH functions as a regulator for selective activation of the IRE1α branch of the unfolded protein response. PRKCSH boosts ER stress-mediated autophosphorylation and oligomerization of IRE1α through mutual interaction, contributing to induction of tumor-promoting factors and tumor resistance to ER stress.","method":"Co-immunoprecipitation, IRE1α autophosphorylation and oligomerization assays, XBP1 splicing assay, PRKCSH knockdown/overexpression with ER stress induction","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, biochemical assays of IRE1α activity, loss-of-function with defined pathway readout, multiple methods in single rigorous study","pmids":["31320625"],"is_preprint":false},{"year":2003,"finding":"FGF-1 stimulation induced translocation of 80K-H (PRKCSH) to the cell nucleus in MCF-7 mammary carcinoma cells, as demonstrated by subcellular fractionation, with maximal intranuclear 80K-H observed ~30 minutes after FGF-1 treatment.","method":"Subcellular fractionation, immunostaining, in silico NLS prediction","journal":"The International journal of biological markers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single subcellular fractionation method in one cell line, single lab, no functional validation of nuclear localization","pmids":["12841677"],"is_preprint":false},{"year":2024,"finding":"PRKCSH interacts with IGF1R, extending its half-life and boosting oncogenic IGF1R activation. The PRKCSH-IGF1R axis impaired caspase-8 activation, increased Mcl-1 expression, and inhibited caspase-9, leading to TNFSF resistance in lung cancer cells. PRKCSH deficiency augmented NK cell antitumor effects in a xenograft model.","method":"Co-immunoprecipitation, protein half-life assay, caspase activation assays, Western blot for Mcl-1, tumor xenograft in NIG mice","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional half-life and pathway assays, in vivo xenograft validation, single lab","pmids":["38200153"],"is_preprint":false},{"year":2025,"finding":"PRKCSH inhibition reduced radioresistance in colorectal cancer cells by activating the ER stress IRE1α/XBP1s pathway, which reduced p53 ubiquitination and degradation, enhanced DNA repair, and thereby contributed to radioresistance when PRKCSH was present. PRKCSH depletion suppressed clonogenic survival, promoted apoptosis, and impaired DNA damage repair.","method":"PRKCSH knockdown, clonogenic survival assay, apoptosis assay, DNA damage repair assay, p53 ubiquitination assay, IRE1α/XBP1s pathway analysis, patient-derived organoid models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (IRE1α/XBP1s-p53 axis) and multiple functional readouts, single lab","pmids":["40189587"],"is_preprint":false},{"year":2025,"finding":"PRKCSH deficiency reduced basal IRE1α phosphorylation but caused exaggerated IRE1α activation under ER stress (increased XBP1s and p-JNK signaling). PRKCSH-KO cancer cells suppressed IL-6 and IL-8 secretion, promoted M1 macrophage polarization (increased CD86+ macrophages), and showed increased susceptibility to ER stress-induced apoptosis and ferroptosis with impaired autophagy.","method":"CRISPR/Cas9-mediated gene deletion, cytokine profiling, macrophage co-culture, flow cytometry, zebrafish xenograft, IRE1α phosphorylation assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal functional readouts and in vivo zebrafish validation, single lab","pmids":["41350724"],"is_preprint":false},{"year":2024,"finding":"PRKCSH (80K-H) was found to interact with myoclonin1 (EFHC1 protein), and both proteins co-localize at choroid plexus and ependymal cells together with IP3R1. This interaction places PRKCSH in a complex modulating ER-Ca2+ homeostasis in conjunction with IP3Rs.","method":"Co-immunoprecipitation, immunofluorescence co-localization, Ca2+ measurement in Efhc1-deficient mouse cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in preprint, limited functional follow-up for PRKCSH specifically","pmids":["bio_10.1101_2024.07.01.601633"],"is_preprint":true}],"current_model":"PRKCSH (80K-H/hepatocystin) is an ER-resident regulatory beta-subunit of glucosidase II that functions as a chaperone-like molecule and Ca2+ sensor: it binds and protects TRPP2/polycystin-2 from Herp-mediated ERAD, directly enhances IP3R-mediated Ca2+ release via EF-hand-dependent Ca2+ sensing, regulates TRPV5 channel activity through EF-hand Ca2+ binding, boosts IRE1α autophosphorylation and oligomerization to selectively amplify the IRE1α/XBP1s UPR branch, extends IGF1R half-life to promote oncogenic signaling and TNFSF resistance, participates in FGF/GRB-2 and PKCzeta/munc18c signaling cascades, and loss-of-function mutations cause autosomal dominant polycystic liver disease through a two-hit cellular recessive mechanism involving loss of hepatocystin in cyst epithelium."},"narrative":{"mechanistic_narrative":"PRKCSH (80K-H/hepatocystin) is an endoplasmic reticulum-resident, EF-hand-containing protein that functions as a Ca2+ sensor and chaperone-like regulator of ER membrane channels and stress signaling [PMID:15100231, PMID:18990696]. It localizes predominantly to the ER in co-localization with calnexin, with partial distribution to endocytic compartments [PMID:10684806, PMID:12750905]. Through its two EF-hand structures it binds Ca2+ directly and regulates the epithelial Ca2+ channel TRPV5, while EF-hand inactivation alters channel sensitivity to intracellular Ca2+ without affecting channel surface localization [PMID:15100231]; purified PRKCSH similarly enhances IP3R1-mediated Ca2+ release in reconstituted microsomes and living cells [PMID:18990696]. PRKCSH acts as a chaperone-like protein for TRPP2/polycystin-2, binding its C-terminal domain and antagonizing Herp-mediated ubiquitination to protect TRPP2 from ER-associated degradation, and PRKCSH and TRPP2 are reciprocally epistatic in zebrafish cystogenesis assays [PMID:19801576]. In ER stress signaling, PRKCSH binds IRE1α and boosts its autophosphorylation and oligomerization to selectively amplify the IRE1α/XBP1s branch of the unfolded protein response, a function repeatedly linked to tumor cell survival, radioresistance, and inflammatory cytokine output [PMID:31320625, PMID:40189587, PMID:41350724]. PRKCSH additionally extends IGF1R half-life to drive oncogenic signaling and resistance to TNF-superfamily-induced apoptosis [PMID:38200153], and participates in insulin-responsive PKCzeta-munc18c complexes promoting GLUT4 translocation [PMID:15707389]. Germline loss-of-function splice-site mutations in PRKCSH cause autosomal dominant polycystic liver disease, in which cyst epithelium specifically loses hepatocystin, consistent with a cellular recessive two-hit mechanism [PMID:12577059, PMID:12529853, PMID:18224332].","teleology":[{"year":1996,"claim":"Established the first functional contexts for the 80K-H PKC substrate, placing it at the cell surface as an AGE-binding component and downstream of the FGF receptor in growth-factor signaling.","evidence":"Protein sequencing, AGE-ligand binding and antibody-inhibition assays, plus 2D-PAGE microsequencing and GRB-2 GST pulldown in FGF-stimulated fibroblasts","pmids":["8855306","8621453"],"confidence":"Medium","gaps":["Surface AGE-receptor role hard to reconcile with later ER localization","No structural basis for GRB-2 binding or FGFR-dependent phosphorylation defined"]},{"year":2000,"claim":"Defined the protein's predominant subcellular home, showing the bovine ortholog resides in the ER with calnexin and partially in endocytic compartments, reframing it as an intracellular transport-associated protein.","evidence":"Cell fractionation, calnexin co-localization, endoglycosidase H treatment, and immunoprecipitation of metabolically labeled cells","pmids":["10684806","12750905"],"confidence":"Medium","gaps":["Identity of the 116/48.5/26.5-kDa interactors not resolved","Functional role in transport not directly tested"]},{"year":2003,"claim":"Identified PRKCSH as the causative gene for autosomal dominant polycystic liver disease, anchoring its physiological importance to biliary epithelial homeostasis.","evidence":"Genetic linkage mapping, direct sequencing, and segregation analysis in PCLD families across two independent studies","pmids":["12577059","12529853"],"confidence":"High","gaps":["Molecular consequence linking loss-of-function to cyst formation not established at this stage","Cell-of-origin and cell-autonomy unresolved"]},{"year":2004,"claim":"Revealed PRKCSH as a direct Ca2+ sensor through its EF-hands, showing it tunes TRPV5 channel activity and feedback inhibition without altering channel trafficking.","evidence":"Co-immunoprecipitation, EF-hand mutant Ca2+ binding assays, and electrophysiology with 80K-H mutants","pmids":["15100231"],"confidence":"High","gaps":["Whether EF-hand Ca2+ sensing generalizes to other channels not yet tested","Stoichiometry of the 80K-H-TRPV5 interaction unknown"]},{"year":2005,"claim":"Connected PRKCSH to insulin-responsive metabolic signaling by showing it forms an insulin-induced PKCzeta-80K-H-munc18c complex that promotes GLUT4 translocation and glucose uptake.","evidence":"Yeast two-hybrid, GST pulldown domain mapping, endogenous reciprocal Co-IP, and GLUT4 translocation/glucose uptake assays","pmids":["15707389"],"confidence":"High","gaps":["How an ER protein engages plasma-membrane GLUT4 machinery not mechanistically reconciled","Relationship of this pathway to its ER chaperone role unclear"]},{"year":2008,"claim":"Extended the Ca2+-sensor role to IP3R1 by demonstrating purified PRKCSH directly enhances IP3-induced Ca2+ release, and localized PRKCSH loss specifically to cyst epithelium to support a two-hit cystogenesis mechanism.","evidence":"Yeast two-hybrid, in vitro reconstitution of cerebellar microsome Ca2+ release, live-cell imaging, plus immunolocalization in PCLD versus normal liver","pmids":["18990696","18224332"],"confidence":"High","gaps":["EF-hand dependence of IP3R1 enhancement not directly mapped in this work","Direct demonstration of biallelic somatic inactivation in cysts not shown"]},{"year":2010,"claim":"Provided the leading mechanistic explanation for PCLD by showing PRKCSH is a chaperone-like protein that protects polycystin-2/TRPP2 from Herp-mediated ERAD, with in vivo epistasis linking the two.","evidence":"Reciprocal Co-IP, ubiquitination assay, and zebrafish knockdown/overexpression epistasis rescue","pmids":["19801576"],"confidence":"High","gaps":["Whether TRPP2 destabilization fully accounts for human liver cystogenesis not proven","Direct enzymatic/glucosidase contribution to TRPP2 protection not dissected"]},{"year":2012,"claim":"Identified TRIM67 as a negative regulator that drives PRKCSH proteasomal degradation, linking PRKCSH levels to Ras signaling, proliferation, and neuritogenesis.","evidence":"Co-IP, overexpression and siRNA knockdown with proliferation and neuritogenesis assays in neuroblastoma cells","pmids":["22337885"],"confidence":"Medium","gaps":["Mechanism linking PRKCSH to Ras pathway not defined","Generality beyond neuroblastoma cells untested"]},{"year":2013,"claim":"Showed hepatocystin restrains hepatitis B virus by directly binding HBx through its mannose-6-phosphate receptor homology domain and accelerating ubiquitin-independent HBx degradation.","evidence":"AP-MS, Co-IP, deletion-mutant domain mapping, proteasome inhibitor studies, and HBV replication assays","pmids":["23644164"],"confidence":"High","gaps":["Physiological relevance in infected hepatocytes in vivo not established","Mechanism of ubiquitin-independent degradation undefined"]},{"year":2019,"claim":"Established PRKCSH as a selective amplifier of the IRE1α/XBP1s UPR branch, boosting IRE1α autophosphorylation and oligomerization to promote tumor resistance to ER stress.","evidence":"Reciprocal Co-IP, IRE1α autophosphorylation/oligomerization and XBP1 splicing assays with PRKCSH knockdown/overexpression","pmids":["31320625"],"confidence":"High","gaps":["Why amplification is selective for IRE1α over PERK/ATF6 not fully resolved","Structural basis of the PRKCSH-IRE1α interaction unknown"]},{"year":2024,"claim":"Linked PRKCSH to oncogenic receptor signaling and apoptosis evasion by showing it stabilizes IGF1R and confers TNFSF resistance, with deficiency enhancing NK-cell antitumor activity.","evidence":"Co-IP, protein half-life and caspase activation assays, and tumor xenograft in immunodeficient mice","pmids":["38200153"],"confidence":"Medium","gaps":["Direct versus indirect basis of IGF1R stabilization not separated","Whether ER chaperone activity underlies IGF1R protection untested"]},{"year":2025,"claim":"Connected the PRKCSH-IRE1α axis to therapy resistance and tumor immunity, showing PRKCSH supports radioresistance via IRE1α/XBP1s-mediated p53 stabilization and DNA repair, while its loss reprograms the immune microenvironment and sensitizes cells to ER-stress death.","evidence":"Knockdown/CRISPR-KO clonogenic, apoptosis, ferroptosis, DNA repair, and p53 ubiquitination assays plus cytokine profiling, macrophage co-culture, organoid and zebrafish xenograft models","pmids":["40189587","41350724"],"confidence":"Medium","gaps":["Reconciling reduced basal but exaggerated stress-induced IRE1α activation upon loss not fully mechanistic","Tissue-specificity of the p53 and immune effects unresolved"]},{"year":null,"claim":"How PRKCSH's distinct activities — EF-hand Ca2+ sensing, ERAD-protective chaperone function, and IRE1α amplification — are integrated and selectively deployed across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model links the Ca2+-sensor, chaperone, and UPR-amplifier roles","Mechanism partitioning PRKCSH between ER channel regulation and stress signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,12,9]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,4,8,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12,15,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,8]}],"complexes":["PKCzeta-80K-H-munc18c complex"],"partners":["TRPV5","ITPR1","PKN/PRKCZ","STXBP4","PKD2","HERPUD1","ERN1","IGF1R"],"other_free_text":[]}},"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},{"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},{"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},{"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},{"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},{"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},{"pmid":"16835903","id":"PMC_16835903","title":"Extensive mutational analysis of PRKCSH and SEC63 broadens the 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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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"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":1,"is_preprint":false},{"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},{"pmid":"42119524","id":"PMC_42119524","title":"Clinical and immune features associated with chromosome 13q deletion and PRKCSH downregulation in newly diagnosed multiple myeloma.","date":"2026","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/42119524","citation_count":0,"is_preprint":false},{"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21230,"output_tokens":5085,"usd":0.069983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13362,"output_tokens":4488,"usd":0.089505,"stage2_stop_reason":"end_turn"},"total_usd":0.159488,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The AGE receptor component p90 (80K-H/PRKCSH) was identified as identical to the previously described 80K-H protein kinase C substrate. Immunostaining and flow cytometry demonstrated surface expression on multiple cell types, and immune IgG raised to recombinant 80K-H inhibited AGE-BSA binding to cell membranes in a dose-dependent manner, establishing 80K-H as a functional AGE-binding protein.\",\n      \"method\": \"Protein sequencing, immunoprecipitation, AGE-ligand binding assay, flow cytometry, antibody inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation and functional inhibition by antibody in a single lab, multiple orthogonal methods\",\n      \"pmids\": [\"8855306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"80K-H (PRKCSH) was identified as the tyrosine-phosphorylated protein p90 in FGF-stimulated fibroblasts. 80K-H was specifically tyrosine-phosphorylated within 30 seconds of FGF (but not other growth factors) stimulation and was found to bind specifically to GRB-2-GST fusion protein, placing it downstream of FGF receptor in a signaling pathway.\",\n      \"method\": \"2D-PAGE microsequencing, Western blot with anti-phosphotyrosine antibody, immunoprecipitation, GST pulldown with GRB-2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8621453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Germline loss-of-function mutations in PRKCSH (splice-acceptor and splice-donor site mutations) were identified as the genetic cause of autosomal dominant polycystic liver disease (PCLD), establishing PRKCSH as necessary for normal biliary epithelial homeostasis.\",\n      \"method\": \"Genetic linkage mapping, direct sequencing of PRKCSH in PCLD families, segregation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently across two simultaneous studies (PMIDs 12577059 and 12529853) using sequencing and segregation analysis in multiple families\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Bovine ortholog VASAP-60 (80K-H/PRKCSH) was localized predominantly to the endoplasmic reticulum (co-localizing with calnexin) and partially to endocytic compartments, and was found in a membrane fraction unglycosylated. Immunoprecipitation demonstrated interaction with 116-, 48.5-, and 26.5-kDa proteins, suggesting a role in intracellular transport events.\",\n      \"method\": \"Cell fractionation, immunocytochemistry with ER marker co-localization, endoglycosidase H treatment, immunoprecipitation of metabolically labeled cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional context, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10684806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VASAP-60/80K-H (PRKCSH) was localized to the perinuclear ER (co-localizing with calnexin) and partially to endocytic/vacuolar compartments in bovine tissues and cell lines. A 58-kDa proteolytically processed form was identified, and the protein's anomalous migration (88 kDa observed vs. 60.1 kDa predicted) was attributed to its glutamic/aspartic acid-rich central region.\",\n      \"method\": \"Immunocytochemistry with calnexin co-localization, immunohistochemistry, immunoblotting, SDS-PAGE analysis of recombinant domain fragments\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization with functional structural insight, single lab, orthogonal methods\",\n      \"pmids\": [\"12750905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"80K-H (PRKCSH) was identified as a Ca2+ sensor that directly interacts with and regulates the epithelial Ca2+ channel TRPV5. 80K-H directly bound Ca2+ through its two EF-hand structures; inactivation of EF-hands abolished Ca2+ binding and reduced TRPV5-mediated Ca2+ current while increasing TRPV5 sensitivity to intracellular Ca2+, accelerating feedback inhibition. The highly acidic glutamic stretch and the HDEL sequence were also identified as critical determinants for TRPV5 activity. Neither EF-hand inactivation nor other 80K-H mutations altered TRPV5 plasma membrane localization or 80K-H-TRPV5 association.\",\n      \"method\": \"cDNA microarray identification, co-immunoprecipitation, co-localization, Ca2+ binding assay with EF-hand mutants, electrophysiology with 80K-H mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro Ca2+ binding assay with mutagenesis, electrophysiological functional validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"15100231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"80K-H (PRKCSH) was identified as an interactor with PKCzeta via yeast two-hybrid screening, confirmed by GST pulldown showing the N-terminal portion of 80K-H was not required for this interaction. Endogenous co-immunoprecipitation confirmed a physiological PKCzeta-80K-H interaction that was enhanced 3-5-fold by insulin. 80K-H also co-immunoprecipitated with munc18c, forming a PKCzeta-80K-H-munc18c complex upon insulin stimulation. Overexpression of 80K-H constructs stimulated glucose uptake and GLUT4 translocation proportional to their ability to associate with munc18c.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, endogenous co-immunoprecipitation, GLUT4 translocation assay, glucose uptake assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmed in multiple cell types, GST pulldown with domain mapping, functional overexpression assay, multiple orthogonal methods\",\n      \"pmids\": [\"15707389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"80K-H (PRKCSH) was identified as a novel interactor with the C-terminal tail of IP3R type 1 via yeast two-hybrid screening. Direct in vitro interaction was confirmed by pull-down assay. 80K-H co-immunoprecipitated with IP3R1 in cell lysates and co-localized with IP3R1 in COS-7 cells and hippocampal neurons. Purified recombinant 80K-H directly enhanced IP3-induced Ca2+ release activity in mouse cerebellar microsomes, and 80K-H regulated ATP-induced Ca2+ release in living cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, immunocytochemistry, Ca2+ release assay with cerebellar microsomes, live-cell Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of Ca2+ release enhancement with purified recombinant protein, validated by multiple orthogonal methods including co-IP and live-cell assays\",\n      \"pmids\": [\"18990696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hepatocystin (PRKCSH) and Sec63p were both localized predominantly to the endoplasmic reticulum by cell fractionation, immunofluorescence, and immunohistochemistry. Cysts from PRKCSH mutation carriers specifically lacked hepatocystin expression, while all cysts regardless of mutation status expressed Sec63p, supporting a cellular recessive (two-hit) mechanism for cystogenesis in PRKCSH-associated PCLD.\",\n      \"method\": \"Cell fractionation, immunofluorescence, immunohistochemistry of PCLD and normal liver tissue\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization with functional consequence (loss of hepatocystin in cysts), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18224332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKCSH (hepatocystin) was shown to bind the C-terminal domain of TRPP2/polycystin-2 and co-localize with TRPP2 within the ER. PRKCSH interacts with Herp and inhibits Herp-mediated ubiquitination of TRPP2, thereby functioning as a chaperone-like molecule that protects TRPP2 against ER-associated degradation (ERAD). Over-expression or depletion of PRKCSH in zebrafish embryos caused pronephric cysts, and TRPP2 overexpression could rescue PRKCSH depletion phenotypes (and vice versa), establishing epistasis.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, ubiquitination assay, zebrafish knockdown/overexpression with epistasis rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo epistasis rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19801576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM67 was found to interact with 80K-H (PRKCSH) and induce its proteasomal degradation. Ectopic TRIM67 expression degraded endogenous 80K-H, attenuated cell proliferation, and enhanced neuritogenesis in N1E-115 neuroblastoma cells. Knockdown of 80K-H alone phenocopied TRIM67 overexpression, and these changes were linked to attenuation of Ras-mediated signaling.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, cell proliferation assay, neuritogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function phenocopy with defined cellular readouts, single lab\",\n      \"pmids\": [\"22337885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocystin/PRKCSH directly interacts with HBV X protein (HBx): the HBx C-terminus (aa 110-154) binds the mannose 6-phosphate receptor homology domain (aa 419-525) of hepatocystin. Hepatocystin overexpression accelerated HBx degradation via a ubiquitin-independent proteasomal pathway, significantly inhibited HBV DNA replication and HBs antigen expression in a manner dependent on the HBx-binding domain of hepatocystin.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, immunocytochemistry, domain mapping with deletion mutants, proteasome inhibitor studies, HBV replication assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by deletion mutants, functional HBV replication assay, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23644164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRKCSH functions as a regulator for selective activation of the IRE1α branch of the unfolded protein response. PRKCSH boosts ER stress-mediated autophosphorylation and oligomerization of IRE1α through mutual interaction, contributing to induction of tumor-promoting factors and tumor resistance to ER stress.\",\n      \"method\": \"Co-immunoprecipitation, IRE1α autophosphorylation and oligomerization assays, XBP1 splicing assay, PRKCSH knockdown/overexpression with ER stress induction\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, biochemical assays of IRE1α activity, loss-of-function with defined pathway readout, multiple methods in single rigorous study\",\n      \"pmids\": [\"31320625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FGF-1 stimulation induced translocation of 80K-H (PRKCSH) to the cell nucleus in MCF-7 mammary carcinoma cells, as demonstrated by subcellular fractionation, with maximal intranuclear 80K-H observed ~30 minutes after FGF-1 treatment.\",\n      \"method\": \"Subcellular fractionation, immunostaining, in silico NLS prediction\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single subcellular fractionation method in one cell line, single lab, no functional validation of nuclear localization\",\n      \"pmids\": [\"12841677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCSH interacts with IGF1R, extending its half-life and boosting oncogenic IGF1R activation. The PRKCSH-IGF1R axis impaired caspase-8 activation, increased Mcl-1 expression, and inhibited caspase-9, leading to TNFSF resistance in lung cancer cells. PRKCSH deficiency augmented NK cell antitumor effects in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assay, caspase activation assays, Western blot for Mcl-1, tumor xenograft in NIG mice\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional half-life and pathway assays, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"38200153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCSH inhibition reduced radioresistance in colorectal cancer cells by activating the ER stress IRE1α/XBP1s pathway, which reduced p53 ubiquitination and degradation, enhanced DNA repair, and thereby contributed to radioresistance when PRKCSH was present. PRKCSH depletion suppressed clonogenic survival, promoted apoptosis, and impaired DNA damage repair.\",\n      \"method\": \"PRKCSH knockdown, clonogenic survival assay, apoptosis assay, DNA damage repair assay, p53 ubiquitination assay, IRE1α/XBP1s pathway analysis, patient-derived organoid models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (IRE1α/XBP1s-p53 axis) and multiple functional readouts, single lab\",\n      \"pmids\": [\"40189587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKCSH deficiency reduced basal IRE1α phosphorylation but caused exaggerated IRE1α activation under ER stress (increased XBP1s and p-JNK signaling). PRKCSH-KO cancer cells suppressed IL-6 and IL-8 secretion, promoted M1 macrophage polarization (increased CD86+ macrophages), and showed increased susceptibility to ER stress-induced apoptosis and ferroptosis with impaired autophagy.\",\n      \"method\": \"CRISPR/Cas9-mediated gene deletion, cytokine profiling, macrophage co-culture, flow cytometry, zebrafish xenograft, IRE1α phosphorylation assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal functional readouts and in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"41350724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKCSH (80K-H) was found to interact with myoclonin1 (EFHC1 protein), and both proteins co-localize at choroid plexus and ependymal cells together with IP3R1. This interaction places PRKCSH in a complex modulating ER-Ca2+ homeostasis in conjunction with IP3Rs.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, Ca2+ measurement in Efhc1-deficient mouse cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in preprint, limited functional follow-up for PRKCSH specifically\",\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 beta-subunit of glucosidase II that functions as a chaperone-like molecule and Ca2+ sensor: it binds and protects TRPP2/polycystin-2 from Herp-mediated ERAD, directly enhances IP3R-mediated Ca2+ release via EF-hand-dependent Ca2+ sensing, regulates TRPV5 channel activity through EF-hand Ca2+ binding, boosts IRE1α autophosphorylation and oligomerization to selectively amplify the IRE1α/XBP1s UPR branch, extends IGF1R half-life to promote oncogenic signaling and TNFSF resistance, participates in FGF/GRB-2 and PKCzeta/munc18c signaling cascades, and loss-of-function mutations cause autosomal dominant polycystic liver disease through a two-hit cellular recessive mechanism involving loss of hepatocystin in cyst epithelium.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKCSH (80K-H/hepatocystin) is an endoplasmic reticulum-resident, EF-hand-containing protein that functions as a Ca2+ sensor and chaperone-like regulator of ER membrane channels and stress signaling [#5, #7]. It localizes predominantly to the ER in co-localization with calnexin, with partial distribution to endocytic compartments [#3, #4]. Through its two EF-hand structures it binds Ca2+ directly and regulates the epithelial Ca2+ channel TRPV5, while EF-hand inactivation alters channel sensitivity to intracellular Ca2+ without affecting channel surface localization [#5]; purified PRKCSH similarly enhances IP3R1-mediated Ca2+ release in reconstituted microsomes and living cells [#7]. PRKCSH acts as a chaperone-like protein for TRPP2/polycystin-2, binding its C-terminal domain and antagonizing Herp-mediated ubiquitination to protect TRPP2 from ER-associated degradation, and PRKCSH and TRPP2 are reciprocally epistatic in zebrafish cystogenesis assays [#9]. In ER stress signaling, PRKCSH binds IRE1\\u03b1 and boosts its autophosphorylation and oligomerization to selectively amplify the IRE1\\u03b1/XBP1s branch of the unfolded protein response, a function repeatedly linked to tumor cell survival, radioresistance, and inflammatory cytokine output [#12, #15, #16]. PRKCSH additionally extends IGF1R half-life to drive oncogenic signaling and resistance to TNF-superfamily-induced apoptosis [#14], and participates in insulin-responsive PKCzeta-munc18c complexes promoting GLUT4 translocation [#6]. Germline loss-of-function splice-site mutations in PRKCSH cause autosomal dominant polycystic liver disease, in which cyst epithelium specifically loses hepatocystin, consistent with a cellular recessive two-hit mechanism [#2, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the first functional contexts for the 80K-H PKC substrate, placing it at the cell surface as an AGE-binding component and downstream of the FGF receptor in growth-factor signaling.\",\n      \"evidence\": \"Protein sequencing, AGE-ligand binding and antibody-inhibition assays, plus 2D-PAGE microsequencing and GRB-2 GST pulldown in FGF-stimulated fibroblasts\",\n      \"pmids\": [\"8855306\", \"8621453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Surface AGE-receptor role hard to reconcile with later ER localization\", \"No structural basis for GRB-2 binding or FGFR-dependent phosphorylation defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the protein's predominant subcellular home, showing the bovine ortholog resides in the ER with calnexin and partially in endocytic compartments, reframing it as an intracellular transport-associated protein.\",\n      \"evidence\": \"Cell fractionation, calnexin co-localization, endoglycosidase H treatment, and immunoprecipitation of metabolically labeled cells\",\n      \"pmids\": [\"10684806\", \"12750905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the 116/48.5/26.5-kDa interactors not resolved\", \"Functional role in transport not directly tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified PRKCSH as the causative gene for autosomal dominant polycystic liver disease, anchoring its physiological importance to biliary epithelial homeostasis.\",\n      \"evidence\": \"Genetic linkage mapping, direct sequencing, and segregation analysis in PCLD families across two independent studies\",\n      \"pmids\": [\"12577059\", \"12529853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular consequence linking loss-of-function to cyst formation not established at this stage\", \"Cell-of-origin and cell-autonomy unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed PRKCSH as a direct Ca2+ sensor through its EF-hands, showing it tunes TRPV5 channel activity and feedback inhibition without altering channel trafficking.\",\n      \"evidence\": \"Co-immunoprecipitation, EF-hand mutant Ca2+ binding assays, and electrophysiology with 80K-H mutants\",\n      \"pmids\": [\"15100231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EF-hand Ca2+ sensing generalizes to other channels not yet tested\", \"Stoichiometry of the 80K-H-TRPV5 interaction unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected PRKCSH to insulin-responsive metabolic signaling by showing it forms an insulin-induced PKCzeta-80K-H-munc18c complex that promotes GLUT4 translocation and glucose uptake.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown domain mapping, endogenous reciprocal Co-IP, and GLUT4 translocation/glucose uptake assays\",\n      \"pmids\": [\"15707389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER protein engages plasma-membrane GLUT4 machinery not mechanistically reconciled\", \"Relationship of this pathway to its ER chaperone role unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the Ca2+-sensor role to IP3R1 by demonstrating purified PRKCSH directly enhances IP3-induced Ca2+ release, and localized PRKCSH loss specifically to cyst epithelium to support a two-hit cystogenesis mechanism.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro reconstitution of cerebellar microsome Ca2+ release, live-cell imaging, plus immunolocalization in PCLD versus normal liver\",\n      \"pmids\": [\"18990696\", \"18224332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EF-hand dependence of IP3R1 enhancement not directly mapped in this work\", \"Direct demonstration of biallelic somatic inactivation in cysts not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the leading mechanistic explanation for PCLD by showing PRKCSH is a chaperone-like protein that protects polycystin-2/TRPP2 from Herp-mediated ERAD, with in vivo epistasis linking the two.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, and zebrafish knockdown/overexpression epistasis rescue\",\n      \"pmids\": [\"19801576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRPP2 destabilization fully accounts for human liver cystogenesis not proven\", \"Direct enzymatic/glucosidase contribution to TRPP2 protection not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified TRIM67 as a negative regulator that drives PRKCSH proteasomal degradation, linking PRKCSH levels to Ras signaling, proliferation, and neuritogenesis.\",\n      \"evidence\": \"Co-IP, overexpression and siRNA knockdown with proliferation and neuritogenesis assays in neuroblastoma cells\",\n      \"pmids\": [\"22337885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PRKCSH to Ras pathway not defined\", \"Generality beyond neuroblastoma cells untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed hepatocystin restrains hepatitis B virus by directly binding HBx through its mannose-6-phosphate receptor homology domain and accelerating ubiquitin-independent HBx degradation.\",\n      \"evidence\": \"AP-MS, Co-IP, deletion-mutant domain mapping, proteasome inhibitor studies, and HBV replication assays\",\n      \"pmids\": [\"23644164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance in infected hepatocytes in vivo not established\", \"Mechanism of ubiquitin-independent degradation undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PRKCSH as a selective amplifier of the IRE1\\u03b1/XBP1s UPR branch, boosting IRE1\\u03b1 autophosphorylation and oligomerization to promote tumor resistance to ER stress.\",\n      \"evidence\": \"Reciprocal Co-IP, IRE1\\u03b1 autophosphorylation/oligomerization and XBP1 splicing assays with PRKCSH knockdown/overexpression\",\n      \"pmids\": [\"31320625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why amplification is selective for IRE1\\u03b1 over PERK/ATF6 not fully resolved\", \"Structural basis of the PRKCSH-IRE1\\u03b1 interaction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked PRKCSH to oncogenic receptor signaling and apoptosis evasion by showing it stabilizes IGF1R and confers TNFSF resistance, with deficiency enhancing NK-cell antitumor activity.\",\n      \"evidence\": \"Co-IP, protein half-life and caspase activation assays, and tumor xenograft in immunodeficient mice\",\n      \"pmids\": [\"38200153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect basis of IGF1R stabilization not separated\", \"Whether ER chaperone activity underlies IGF1R protection untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected the PRKCSH-IRE1\\u03b1 axis to therapy resistance and tumor immunity, showing PRKCSH supports radioresistance via IRE1\\u03b1/XBP1s-mediated p53 stabilization and DNA repair, while its loss reprograms the immune microenvironment and sensitizes cells to ER-stress death.\",\n      \"evidence\": \"Knockdown/CRISPR-KO clonogenic, apoptosis, ferroptosis, DNA repair, and p53 ubiquitination assays plus cytokine profiling, macrophage co-culture, organoid and zebrafish xenograft models\",\n      \"pmids\": [\"40189587\", \"41350724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciling reduced basal but exaggerated stress-induced IRE1\\u03b1 activation upon loss not fully mechanistic\", \"Tissue-specificity of the p53 and immune effects unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRKCSH's distinct activities — EF-hand Ca2+ sensing, ERAD-protective chaperone function, and IRE1\\u03b1 amplification — are integrated and selectively deployed across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model links the Ca2+-sensor, chaperone, and UPR-amplifier roles\", \"Mechanism partitioning PRKCSH between ER channel regulation and stress signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 12, 9]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 4, 8, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 15, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [\"PKCzeta-80K-H-munc18c complex\"],\n    \"partners\": [\"TRPV5\", \"ITPR1\", \"PKN/PRKCZ\", \"STXBP4\", \"PKD2\", \"HERPUD1\", \"ERN1\", \"IGF1R\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}