id: P27797 gene_symbol: CALR product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'Calreticulin (CALR) is the soluble endoplasmic reticulum-luminal lectin chaperone that, together with the membrane-bound paralog calnexin, constitutes the central calnexin/calreticulin cycle of ER glycoprotein quality control. Its globular lectin domain binds monoglucosylated N-glycans (Glc1Man9GlcNAc2) on nearly all nascent glycoproteins, while its extended proline-rich P domain recruits the oxidoreductase ERp57 (PDIA3) and the peptidyl-prolyl isomerase cyclophilin B to promote folding, oligomeric assembly, and retention of incorrectly folded glycoproteins, triaging terminally misfolded clients toward degradation. Calreticulin is a major high-capacity, low-affinity calcium-binding protein that regulates ER calcium storage and homeostasis. It is a key chaperone in the major histocompatibility complex (MHC) class I peptide loading complex, where it stabilizes peptide-receptive MHC I and couples optimal epitope selection to glycan processing. Beyond the ER, calreticulin has well-documented secondary roles: a cell-surface and extracellular "eat-me" signal that promotes phagocytic clearance of apoptotic and stressed cells (immunogenic cell death), C1q/complement interactions, and additional context-specific cytosolic and nuclear activities.' existing_annotations: - term: id: GO:0006457 label: protein folding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Protein folding is a core biological process for calreticulin in the calnexin/calreticulin cycle. action: ACCEPT reason: Phylogenetic transfer agrees with extensive evidence that calreticulin assists folding of nascent glycoproteins in the ER. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Calcium-binding chaperone that promotes folding, oligomeric - term: id: GO:0036503 label: ERAD pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: The calnexin/calreticulin cycle triages terminally misfolded glycoproteins toward ER-associated degradation, supporting participation in the ERAD pathway. action: ACCEPT reason: Quality-control retention and triage of non-native clients is an established core role. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Calcium-binding chaperone that promotes folding, oligomeric - term: id: GO:0005509 label: calcium ion binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Calcium ion binding is a core conserved molecular function; calreticulin is the major high-capacity ER Ca2+-binding protein. action: ACCEPT reason: Well-supported by biochemistry and the conserved calreticulin-family Ca2+-binding domains. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0005509 label: calcium ion binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic calcium ion binding annotation duplicates the core conserved molecular function. action: ACCEPT reason: Consistent with experimental and phylogenetic evidence for Ca2+ binding. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: A cytoplasmic pool of calreticulin exists (cytosolic moonlighting), but it is non-core relative to the ER-luminal chaperone function. action: KEEP_AS_NON_CORE reason: Cytosolic calreticulin is documented for moonlighting roles, but the bulk functional protein is ER-luminal. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: cytosol and extracellular matrix (PubMed:10358038) - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: ER localization is the core compartment for calreticulin. action: ACCEPT reason: Calreticulin is a resident ER-luminal protein. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: ER lumen is the precise core localization of this soluble chaperone. action: ACCEPT reason: Calreticulin bears a KDEL retention signal and resides in the ER lumen. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: A cytosolic pool supports moonlighting functions but is non-core. action: KEEP_AS_NON_CORE reason: Cytosolic calreticulin is documented but secondary to the ER chaperone role. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: cytosol and extracellular matrix (PubMed:10358038) - term: id: GO:0006457 label: protein folding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Electronic protein folding annotation duplicates the core folding role. action: ACCEPT reason: Consistent with experimental and phylogenetic evidence for chaperone-assisted folding. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways. - term: id: GO:0009986 label: cell surface evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cell-surface calreticulin is real (eat-me signal, T-cell surface) but non-core relative to ER function. action: KEEP_AS_NON_CORE reason: Surface exposure is a documented secondary localization linked to phagocytic clearance and immune signaling. supported_by: - reference_id: PMID:10358038 supporting_text: the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells - term: id: GO:0012505 label: endomembrane system evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Endomembrane system is correct but uninformatively broad; the precise compartment is the ER lumen. action: MARK_AS_OVER_ANNOTATED reason: Subsumed by the more specific ER lumen annotation. - term: id: GO:0033018 label: sarcoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Sarcoplasmic reticulum lumen is the muscle-cell equivalent of the ER lumen; a valid specialized localization but non-core. action: KEEP_AS_NON_CORE reason: Reflects the ER/SR continuum in muscle; not distinct from the core ER-luminal role. - term: id: GO:0044194 label: cytolytic granule evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Calreticulin is a major constituent of cytolytic (lytic) granules of CTLs; a real but specialized non-core localization. action: KEEP_AS_NON_CORE reason: Documented localization in lytic granules, secondary to the ER chaperone function. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Cytolytic granule - term: id: GO:0060473 label: cortical granule evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cortical granule localization (oocytes) is an ortholog-supported specialized pool linked to the block to polyspermy; non-core. action: KEEP_AS_NON_CORE reason: Documented in oocyte cortical granules by similarity; secondary to the ER role. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Cortical granule - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15896298 qualifier: enables review: summary: Bare protein binding (ERp57/beta-amyloid in CSF study) is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Per guidelines, generic protein binding does not convey calreticulin function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17055437 qualifier: enables review: summary: This reflects calreticulin's role in redox-regulated MHC I peptide selection, but bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: The functional content is MHC I peptide loading, captured by PLC terms; generic protein binding adds nothing. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17215244 qualifier: enables review: summary: Generic protein binding from a GPCR-complex study; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18177377 qualifier: enables review: summary: This reflects the calreticulin-MBL interaction (cC1qR/MBL co-receptor), but bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: The MBL/innate-immune interaction is a non-core extracellular role; generic protein binding does not capture it. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19154346 qualifier: enables review: summary: Generic protein binding (GABARAP-calreticulin interface) is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: Generic protein binding from an autophagy-network interactome; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21900206 qualifier: enables review: summary: Generic protein binding from a directed signal-transduction interaction network; uninformative. action: MARK_AS_OVER_ANNOTATED reason: High-throughput interaction; bare protein binding adds no functional information. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25241761 qualifier: enables review: summary: Generic protein binding from a proximity-ligation pathway profiling study; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25277244 qualifier: enables review: summary: Generic protein binding from an Hsp27 functional-landscape study; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26514267 qualifier: enables review: summary: Generic protein binding from a melatonin MT1 presynaptic interactome; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28298427 qualifier: enables review: summary: Generic protein binding from a GPCR interaction-mapping study; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30108113 qualifier: enables review: summary: Generic protein binding from a colorectal-cancer mutation study; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Generic protein binding from a reference binary interactome; uninformative. action: MARK_AS_OVER_ANNOTATED reason: High-throughput interactome hit; bare protein binding adds no functional information. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Generic protein binding from a neurodegenerative-disease interactome; uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36417879 qualifier: enables review: summary: This study shows mutant calreticulin perturbs the glycoproteome, but bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: The functional content is glycoprotein chaperoning; generic protein binding does not capture it. supported_by: - reference_id: PMID:36417879 supporting_text: Calreticulin mutations affect its chaperone function and perturb the glycoproteome. - term: id: GO:0001669 label: acrosomal vesicle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Acrosomal vesicle localization is an ortholog-transferred specialized pool; non-core and weakly supported for human. action: MARK_AS_OVER_ANNOTATED reason: Ortholog phenotype/localization transfer; not part of the core ER function. - term: id: GO:0002502 label: peptide antigen assembly with MHC class I protein complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: MHC class I peptide antigen assembly is a well-supported specialized role of calreticulin in the peptide loading complex. action: KEEP_AS_NON_CORE reason: This is a specialized application of the lectin-chaperone function; supported directly (see IDA from PMID:35948544) but secondary to general glycoprotein folding. supported_by: - reference_id: PMID:35948544 supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan - term: id: GO:0003729 label: mRNA binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: mRNA binding reflects cytosolic moonlighting (e.g. p21, C/EBP mRNAs); documented but non-core for an ER lectin chaperone. action: KEEP_AS_NON_CORE reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role. - term: id: GO:0005506 label: iron ion binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Iron ion binding is an ortholog-transferred metal-binding claim with weak support; not a credible core function. action: MARK_AS_OVER_ANNOTATED reason: Poorly supported metal-binding inference; calreticulin's characterized metal ligand is Ca2+. - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: A secreted/extracellular pool of calreticulin exists but is non-core. action: KEEP_AS_NON_CORE reason: Documented extracellular/secreted localization, secondary to ER function. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Secreted, extracellular space, - term: id: GO:0005635 label: nuclear envelope evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Nuclear envelope localization likely reflects continuity with the ER and a minor nuclear-envelope pool; non-core. action: KEEP_AS_NON_CORE reason: A minor localization, partly reflecting ER/nuclear-envelope continuity. - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Mitochondrial localization is an ortholog-transferred over-call for a soluble ER-luminal chaperone. action: MARK_AS_OVER_ANNOTATED reason: Not supported by direct human evidence; an ER protein is unlikely to be a genuine mitochondrial resident. - term: id: GO:0005790 label: smooth endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Smooth ER is a sub-compartment of the broader ER localization; subsumed by the core ER annotation. action: KEEP_AS_NON_CORE reason: A specific ER sub-compartment; not distinct from the core ER-luminal role. - term: id: GO:0007283 label: spermatogenesis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Spermatogenesis is an ortholog-derived phenotype-transfer over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Phenotype transfer, not a direct molecular function of human calreticulin. - term: id: GO:0009410 label: response to xenobiotic stimulus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to xenobiotic stimulus is a broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Over-broad phenotype/response transfer, not a core function. - term: id: GO:0009897 label: external side of plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: External side of the plasma membrane corresponds to surface-exposed (eat-me) calreticulin; real but non-core. action: KEEP_AS_NON_CORE reason: Surface exposure is documented; secondary to the ER chaperone role. supported_by: - reference_id: PMID:10358038 supporting_text: the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells - term: id: GO:0010628 label: positive regulation of gene expression evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of gene expression is an over-broad downstream/ortholog-transferred effect. action: MARK_AS_OVER_ANNOTATED reason: Over-broad BP not reflecting a direct calreticulin molecular activity. - term: id: GO:0016529 label: sarcoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Sarcoplasmic reticulum is the muscle ER equivalent; a valid specialized localization but non-core. action: KEEP_AS_NON_CORE reason: Reflects ER/SR continuum in muscle; not distinct from the core ER role. - term: id: GO:0030246 label: carbohydrate binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Carbohydrate (monoglucosylated N-glycan) binding is a core molecular function underlying the lectin-chaperone activity. action: ACCEPT reason: Calreticulin is a lectin that binds monoglucosylated glycans on glycoprotein clients. supported_by: - reference_id: PMID:15056662 supporting_text: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin - term: id: GO:0031012 label: extracellular matrix evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Extracellular matrix localization reflects the secreted/extracellular pool; non-core. action: KEEP_AS_NON_CORE reason: Documented extracellular/matrix pool, secondary to ER function. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Secreted, extracellular space, - term: id: GO:0032355 label: response to estradiol evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to estradiol is a broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Over-broad phenotype/response transfer, not a core function. - term: id: GO:0032991 label: protein-containing complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: Generic protein-containing complex membership is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Too general; specific complexes (PLC) are captured elsewhere. - term: id: GO:0033574 label: response to testosterone evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to testosterone is a broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Over-broad phenotype/response transfer, not a core function. - term: id: GO:0034504 label: protein localization to nucleus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Protein localization to nucleus relates to the cytosolic nuclear-export moonlighting role; non-core. action: KEEP_AS_NON_CORE reason: Linked to the documented nuclear-export receptor activity; secondary to ER function. - term: id: GO:0042277 label: peptide binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Peptide binding is consistent with calreticulin's chaperone interactions (e.g. in MHC I peptide loading) but is a broad MF. action: KEEP_AS_NON_CORE reason: Generic peptide binding partially reflects the chaperone/PLC role; retain as non-core rather than core. - term: id: GO:0042562 label: hormone binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Hormone binding is a weakly supported ortholog-transferred MF. action: MARK_AS_OVER_ANNOTATED reason: Not a credible core molecular function; likely derived from steroid-receptor moonlighting reports. - term: id: GO:0042824 label: MHC class I peptide loading complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: Calreticulin is a bona fide component of the MHC class I peptide loading complex. action: KEEP_AS_NON_CORE reason: Well-supported specialized complex membership; secondary to the general glycoprotein-folding core function. supported_by: - reference_id: PMID:35948544 supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan - term: id: GO:0044322 label: endoplasmic reticulum quality control compartment evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Localization to the ER quality control compartment is consistent with calreticulin's retention/triage role. action: ACCEPT reason: Directly aligned with the core ER quality-control function. supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Calcium-binding chaperone that promotes folding, oligomeric - term: id: GO:0045787 label: positive regulation of cell cycle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Positive regulation of cell cycle is an over-broad downstream/ortholog-transferred effect. action: MARK_AS_OVER_ANNOTATED reason: Over-broad BP not reflecting a direct calreticulin activity. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; non-core descriptive localization. action: KEEP_AS_NON_CORE reason: Consistent with perinuclear ER; not a distinct functional compartment. - term: id: GO:0050766 label: positive regulation of phagocytosis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Surface calreticulin acts as an eat-me signal promoting phagocytosis; a real but non-core role. action: KEEP_AS_NON_CORE reason: Well-documented immunogenic-cell-death/eat-me biology; secondary to the ER chaperone function. - term: id: GO:0050821 label: protein stabilization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Protein stabilization captures calreticulin's chaperone-mediated stabilization of folding clients. action: ACCEPT reason: Consistent with experimental evidence (e.g. insulin receptor stabilization) and the core chaperone role. supported_by: - reference_id: PMID:17563366 supporting_text: calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor - term: id: GO:0055007 label: cardiac muscle cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: A cardiac developmental role is documented from calreticulin-knockout mice; an ortholog-supported developmental effect rather than the core human function. action: KEEP_AS_NON_CORE reason: CALR-null mice show essential cardiac developmental defects; retain as non-core developmental role. supported_by: - reference_id: PMID:15474971 supporting_text: Studies on calreticulin knockout mice indicate that the protein is essential in early cardiac development. - term: id: GO:0071257 label: cellular response to electrical stimulus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular response to electrical stimulus is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:0071285 label: cellular response to lithium ion evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular response to lithium ion is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:0090398 label: cellular senescence evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular senescence is a downstream/ortholog-transferred effect (cf. p21 translation control); over-broad. action: MARK_AS_OVER_ANNOTATED reason: Over-broad downstream BP, not a direct calreticulin function. - term: id: GO:0098586 label: cellular response to virus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Cellular response to virus is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:0098794 label: postsynapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Postsynapse localization/activity is an ortholog-transferred neuronal over-call for an ER chaperone. action: MARK_AS_OVER_ANNOTATED reason: Not supported by direct human evidence; not a core function. - term: id: GO:0098978 label: glutamatergic synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Glutamatergic synapse activity is an ortholog-transferred neuronal over-call. action: MARK_AS_OVER_ANNOTATED reason: Not supported by direct human evidence; not a core function. - term: id: GO:1901652 label: response to peptide evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to peptide is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:1903416 label: response to glycoside evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to glycoside is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:1904614 label: response to biphenyl evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Response to biphenyl is an over-broad ortholog-transferred response term. action: MARK_AS_OVER_ANNOTATED reason: Phenotype/response transfer, not a core function. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:35948544 qualifier: is_active_in review: summary: Calreticulin is active in the ER as part of the MHC I peptide loading complex; core compartment of action. action: ACCEPT reason: Direct evidence of calreticulin acting in the ER within the PLC. supported_by: - reference_id: PMID:35948544 supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: IDA original_reference_id: PMID:35948544 qualifier: enables review: summary: In the PLC, calreticulin bridges the MHC I glycan to the editing machinery, consistent with an adaptor/scaffolding molecular function. action: KEEP_AS_NON_CORE reason: Supported within the PLC context; a specialized adaptor role secondary to the lectin-chaperone core function. supported_by: - reference_id: PMID:35948544 supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan - term: id: GO:0042824 label: MHC class I peptide loading complex evidence_type: IDA original_reference_id: PMID:35948544 qualifier: part_of review: summary: Direct structural evidence places calreticulin in the MHC class I peptide loading complex. action: KEEP_AS_NON_CORE reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. supported_by: - reference_id: PMID:35948544 supporting_text: we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Immunofluorescence-based ER localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER localization. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: EXP original_reference_id: PMID:10358038 qualifier: located_in review: summary: Experimental evidence confirms calreticulin in the ER lumen. action: ACCEPT reason: Direct support for the core ER-luminal localization. supported_by: - reference_id: PMID:10358038 supporting_text: Calreticulin is an endoplasmic reticulum resident molecule - term: id: GO:0009986 label: cell surface evidence_type: EXP original_reference_id: PMID:10358038 qualifier: located_in review: summary: Experimental evidence shows surface calreticulin on activated T cells; a real but non-core localization. action: KEEP_AS_NON_CORE reason: Direct demonstration of surface exposure; secondary to the ER role. supported_by: - reference_id: PMID:10358038 supporting_text: the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells - term: id: GO:0033018 label: sarcoplasmic reticulum lumen evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence/orthology-transferred SR lumen localization (muscle ER equivalent); non-core. action: KEEP_AS_NON_CORE reason: Reflects the ER/SR continuum; not distinct from the core ER role. - term: id: GO:0044194 label: cytolytic granule evidence_type: EXP original_reference_id: PMID:8418194 qualifier: located_in review: summary: Calreticulin is experimentally shown to be a major constituent of CTL lytic granules; specialized non-core localization. action: KEEP_AS_NON_CORE reason: Direct evidence for lytic-granule localization; secondary to the ER function. supported_by: - reference_id: PMID:8418194 supporting_text: The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. - term: id: GO:0005509 label: calcium ion binding evidence_type: TAS original_reference_id: PMID:15474971 qualifier: enables review: summary: Calcium ion binding is a core molecular function; calreticulin regulates ER Ca2+ storage. action: ACCEPT reason: Well-supported synthesis source for the core Ca2+-binding function. supported_by: - reference_id: PMID:15474971 supporting_text: The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. - term: id: GO:0002502 label: peptide antigen assembly with MHC class I protein complex evidence_type: IDA original_reference_id: PMID:35948544 qualifier: involved_in review: summary: Direct evidence supports calreticulin's involvement in MHC class I peptide antigen assembly. action: KEEP_AS_NON_CORE reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. supported_by: - reference_id: PMID:35948544 supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan - term: id: GO:0006457 label: protein folding evidence_type: IDA original_reference_id: PMID:17563366 qualifier: involved_in review: summary: Direct evidence supports calreticulin's role in folding/maturation of a glycoprotein client (insulin receptor). action: ACCEPT reason: Core biological process supported by direct experimental data. supported_by: - reference_id: PMID:17563366 supporting_text: both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER - term: id: GO:0044183 label: protein folding chaperone evidence_type: IDA original_reference_id: PMID:17563366 qualifier: enables review: summary: Protein folding chaperone is an accurate core molecular function for calreticulin. action: ACCEPT reason: Calreticulin is a bona fide molecular chaperone for glycoprotein clients. supported_by: - reference_id: PMID:17563366 supporting_text: calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor - term: id: GO:0050821 label: protein stabilization evidence_type: IDA original_reference_id: PMID:17563366 qualifier: involved_in review: summary: Calreticulin stabilizes folding clients (insulin receptor variant); core chaperone-related process. action: ACCEPT reason: Directly supported stabilization of a misfolded client. supported_by: - reference_id: PMID:17563366 supporting_text: CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated. - term: id: GO:0051604 label: protein maturation evidence_type: IDA original_reference_id: PMID:17563366 qualifier: involved_in review: summary: Calreticulin contributes to glycoprotein maturation in the ER; consistent with the core chaperone function. action: ACCEPT reason: Directly supported role in early client maturation. supported_by: - reference_id: PMID:17563366 supporting_text: both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER - term: id: GO:0098553 label: lumenal side of endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8863914 qualifier: located_in review: summary: As a soluble ER-luminal protein, calreticulin functions on the luminal side of the ER membrane. action: ACCEPT reason: Consistent with calreticulin's ER-luminal localization. - term: id: GO:0098553 label: lumenal side of endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8951499 qualifier: located_in review: summary: Luminal-side ER membrane localization (MHC I peptide loading pathway) is accurate. action: ACCEPT reason: Consistent with calreticulin's ER-luminal localization. - term: id: GO:0098553 label: lumenal side of endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-983142 qualifier: located_in review: summary: Luminal-side ER membrane localization (PLC formation) is accurate. action: ACCEPT reason: Consistent with calreticulin's ER-luminal localization. - term: id: GO:0098553 label: lumenal side of endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-983161 qualifier: located_in review: summary: Luminal-side ER membrane localization (PLC dissociation) is accurate. action: ACCEPT reason: Consistent with calreticulin's ER-luminal localization. - term: id: GO:0005840 label: ribosome evidence_type: IDA original_reference_id: PMID:14726956 qualifier: located_in review: summary: Ribosome association reflects cytosolic calreticulin in mRNA-translation regulation (p21); a moonlighting context, non-core. action: KEEP_AS_NON_CORE reason: Linked to cytosolic translational-control moonlighting; not the core ER localization. - term: id: GO:0001849 label: complement component C1q complex binding evidence_type: IPI original_reference_id: PMID:9922153 qualifier: enables review: summary: Calreticulin (cC1qR) binds the C1q complex; a documented immune/extracellular molecular function but non-core. action: KEEP_AS_NON_CORE reason: Specific, supported C1q-binding activity relevant to complement and apoptotic-cell clearance; secondary to the ER chaperone role. supported_by: - reference_id: PMID:9922153 supporting_text: C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin - term: id: GO:0005049 label: nuclear export signal receptor activity evidence_type: IDA original_reference_id: PMID:11149926 qualifier: enables review: summary: Cytosolic calreticulin was reported to act as a nuclear export receptor for the glucocorticoid receptor; a moonlighting activity, non-core. action: KEEP_AS_NON_CORE reason: Documented but specialized cytosolic moonlighting function distinct from the ER chaperone role. supported_by: - reference_id: PMID:11149926 supporting_text: Calreticulin Is a receptor for nuclear export. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17916189 qualifier: enables review: summary: Generic protein binding (GABARAP ligand identification); uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not an informative molecular function. - term: id: GO:0005509 label: calcium ion binding evidence_type: IMP original_reference_id: PMID:21705382 qualifier: enables review: summary: Calcium ion binding is a genuine core function of calreticulin, but the cited reference (PMID:21705382) is a wrong-gene mis-assignment - it concerns Bcl2l10, not CALR, and provides no direct CALR Ca2+-binding measurement. action: ACCEPT reason: The GO term (calcium ion binding) is correct and robustly supported by independent evidence (e.g. PMID:15474971), so the annotation is retained; however the original_reference_id PMID:21705382 is misassigned (it is about Bcl2l10) and this reference error should be corrected at source in GOA. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0045787 label: positive regulation of cell cycle evidence_type: IGI original_reference_id: PMID:14726956 qualifier: acts_upstream_of review: summary: Cell-cycle regulation via competition with CUGBP1 for p21 translation is a cytosolic moonlighting effect; over-broad as a core BP. action: MARK_AS_OVER_ANNOTATED reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function. - term: id: GO:0060473 label: cortical granule evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence/orthology-transferred cortical granule localization (oocytes); non-core specialized pool. action: KEEP_AS_NON_CORE reason: Documented by similarity; secondary to ER function. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:30188326 qualifier: located_in review: summary: Direct ER localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER localization. - term: id: GO:0042824 label: MHC class I peptide loading complex evidence_type: IDA original_reference_id: PMID:21263072 qualifier: part_of review: summary: Direct evidence supports calreticulin as a PLC component (glycan-dependent MHC I assembly). action: KEEP_AS_NON_CORE reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. supported_by: - reference_id: PMID:21263072 supporting_text: Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:10605026 qualifier: enables review: summary: This reflects calreticulin association with HLA-F (an MHC Ib client), but bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: The functional content is MHC I chaperoning; generic protein binding does not capture it. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9640257 qualifier: enables review: summary: This reflects calreticulin association with non-classical MHC class I proteins, but bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: The functional content is MHC I chaperoning; generic protein binding does not capture it. - term: id: GO:0005509 label: calcium ion binding evidence_type: IDA original_reference_id: PMID:21590275 qualifier: enables review: summary: Calcium ion binding is a genuine core function of calreticulin, but the cited reference (PMID:21590275) is a wrong-gene mis-assignment - it is about calreticulin-2/CALR3, not CALR. action: ACCEPT reason: The GO term (calcium ion binding) is correct and robustly supported by independent evidence (e.g. PMID:15474971), so the annotation is retained; however the original_reference_id PMID:21590275 is misassigned (it concerns CALR3) and this reference error should be corrected at source in GOA. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0005635 label: nuclear envelope evidence_type: IDA original_reference_id: PMID:21590275 qualifier: located_in review: summary: Nuclear envelope localization reflects ER/nuclear-envelope continuity; non-core. action: KEEP_AS_NON_CORE reason: A minor localization partly reflecting ER continuity. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IDA original_reference_id: PMID:21590275 qualifier: located_in review: summary: Direct ER lumen localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER-luminal localization. - term: id: GO:0005576 label: extracellular region evidence_type: IMP original_reference_id: PMID:22377355 qualifier: located_in review: summary: Extracellular/secreted calreticulin affecting cell migration; non-core extracellular role. action: KEEP_AS_NON_CORE reason: Documented extracellular activity; secondary to ER function. supported_by: - reference_id: PMID:22377355 supporting_text: Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells. - term: id: GO:0010595 label: positive regulation of endothelial cell migration evidence_type: IMP original_reference_id: PMID:22377355 qualifier: involved_in review: summary: Extracellular calreticulin promotes endothelial cell migration; a context-specific non-core role. action: KEEP_AS_NON_CORE reason: Supported context-specific extracellular activity, not the core ER function. supported_by: - reference_id: PMID:22377355 supporting_text: Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells. - term: id: GO:1901164 label: negative regulation of trophoblast cell migration evidence_type: IMP original_reference_id: PMID:22377355 qualifier: involved_in review: summary: Extracellular calreticulin inhibits trophoblast migration; a context-specific non-core role. action: KEEP_AS_NON_CORE reason: Supported context-specific extracellular activity, not the core ER function. supported_by: - reference_id: PMID:22377355 supporting_text: Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells. - term: id: GO:0008284 label: positive regulation of cell population proliferation evidence_type: IGI original_reference_id: PMID:14726956 qualifier: involved_in review: summary: Proliferation regulation via p21 translation control is a cytosolic moonlighting effect; over-broad as a core BP. action: MARK_AS_OVER_ANNOTATED reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function. - term: id: GO:0017148 label: negative regulation of translation evidence_type: IDA original_reference_id: PMID:14726956 qualifier: involved_in review: summary: Cytosolic calreticulin can repress translation of specific mRNAs (p21); a moonlighting activity, non-core. action: KEEP_AS_NON_CORE reason: Documented cytosolic translational-control moonlighting; secondary to the ER role. supported_by: - reference_id: PMID:14726956 supporting_text: Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate - term: id: GO:0090398 label: cellular senescence evidence_type: IGI original_reference_id: PMID:14726956 qualifier: involved_in review: summary: Senescence is a downstream effect of cytosolic p21 translation control; over-broad. action: MARK_AS_OVER_ANNOTATED reason: Downstream/indirect effect, not a direct calreticulin function. - term: id: GO:0033116 label: endoplasmic reticulum-Golgi intermediate compartment membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8863858 qualifier: located_in review: summary: ERGIC membrane localization reflects trafficking of calreticulin-containing complexes; a minor non-core localization. action: KEEP_AS_NON_CORE reason: Transient trafficking compartment localization; secondary to ER-luminal residence. - term: id: GO:0033116 label: endoplasmic reticulum-Golgi intermediate compartment membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8863914 qualifier: located_in review: summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. action: KEEP_AS_NON_CORE reason: Transient trafficking compartment; secondary to ER residence. - term: id: GO:0033116 label: endoplasmic reticulum-Golgi intermediate compartment membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8951595 qualifier: located_in review: summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. action: KEEP_AS_NON_CORE reason: Transient trafficking compartment; secondary to ER residence. - term: id: GO:0034975 label: protein folding in endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:22013210 qualifier: involved_in review: summary: Protein folding in the ER is the precise core biological process for calreticulin. action: ACCEPT reason: Most accurate BP term for calreticulin's chaperone activity. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways. - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:22572157 qualifier: located_in review: summary: Generic membrane localization is uninformatively broad. action: MARK_AS_OVER_ANNOTATED reason: Subsumed by more specific ER/cell-surface localizations. - term: id: GO:0005925 label: focal adhesion evidence_type: HDA original_reference_id: PMID:21423176 qualifier: located_in review: summary: Focal adhesion localization from a high-throughput proteome; consistent with the integrin-tail interaction but non-core. action: KEEP_AS_NON_CORE reason: Plausible given integrin-tail binding, but high-throughput and secondary to ER function. - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: Generic membrane from an NK-cell membrane proteome; uninformatively broad. action: MARK_AS_OVER_ANNOTATED reason: Subsumed by more specific localizations. - term: id: GO:0005576 label: extracellular region evidence_type: HDA original_reference_id: PMID:16502470 qualifier: located_in review: summary: Extracellular detection in colostrum proteomics; non-core secreted pool. action: KEEP_AS_NON_CORE reason: Documented secreted/extracellular detection; secondary to ER function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15056662 qualifier: enables review: summary: This reflects calreticulin binding monoglucosylated MHC I glycans, more informatively captured as carbohydrate binding than bare protein binding. action: MARK_AS_OVER_ANNOTATED reason: The functional content is glycan-dependent MHC I binding, captured by carbohydrate-binding/PLC terms; generic protein binding adds nothing. supported_by: - reference_id: PMID:15056662 supporting_text: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin - term: id: GO:0005634 label: nucleus evidence_type: HDA original_reference_id: PMID:21630459 qualifier: located_in review: summary: Nuclear detection in a sperm-nucleus proteome; non-core moonlighting/contaminant-prone localization. action: KEEP_AS_NON_CORE reason: A minor nuclear pool consistent with nuclear moonlighting reports; secondary to ER function. - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22658674 qualifier: enables review: summary: RNA binding from a global mRNA-interactome capture; not a credible core molecular function. action: MARK_AS_OVER_ANNOTATED reason: High-throughput RNA-capture; not a genuine primary function for an ER lectin chaperone. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: Exosome detection in parotid-gland proteomics; non-core, likely incidental. action: KEEP_AS_NON_CORE reason: High-throughput exosome detection; secondary to ER function. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:23395171 qualifier: located_in review: summary: Direct ER localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER localization. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:23011799 qualifier: located_in review: summary: Direct ER localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER localization. - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-2247514 qualifier: located_in review: summary: Extracellular calreticulin in scavenger-receptor (SCARF1) clearance pathway; non-core. action: KEEP_AS_NON_CORE reason: Reflects extracellular eat-me/clearance biology; secondary to ER function. - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-2507854 qualifier: located_in review: summary: Extracellular calreticulin in scavenger-receptor (MSR1) clearance pathway; non-core. action: KEEP_AS_NON_CORE reason: Reflects extracellular eat-me/clearance biology; secondary to ER function. - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8951595 qualifier: located_in review: summary: Phagocytic vesicle membrane localization in cross-presentation; non-core specialized localization. action: KEEP_AS_NON_CORE reason: Specialized immune-pathway localization; secondary to ER function. - term: id: GO:0071682 label: endocytic vesicle lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-2247514 qualifier: located_in review: summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. action: KEEP_AS_NON_CORE reason: Reflects extracellular/endocytic clearance biology; secondary to ER function. - term: id: GO:0071682 label: endocytic vesicle lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-2507854 qualifier: located_in review: summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. action: KEEP_AS_NON_CORE reason: Reflects extracellular/endocytic clearance biology; secondary to ER function. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-1791082 qualifier: located_in review: summary: ER lumen localization (calreticulin expression); accurate core compartment. action: ACCEPT reason: Consistent with the core ER-luminal localization. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-535717 qualifier: located_in review: summary: ER lumen localization for the chaperone-client binding step; accurate. action: ACCEPT reason: Consistent with the core ER-luminal localization and function. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-548890 qualifier: located_in review: summary: ER lumen localization for the glucosidase II/release step; accurate. action: ACCEPT reason: Consistent with the core ER-luminal localization and the CNX/CRT cycle. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-901047 qualifier: located_in review: summary: ER lumen localization for ERp57 binding; accurate and functionally central. action: ACCEPT reason: Consistent with calreticulin's ERp57-recruiting role in the ER lumen. - term: id: GO:1900026 label: positive regulation of substrate adhesion-dependent cell spreading evidence_type: IMP original_reference_id: PMID:11859136 qualifier: involved_in review: summary: Calreticulin (with C1q receptors/integrins) promotes endothelial cell adhesion/spreading; a context-specific extracellular role, non-core. action: KEEP_AS_NON_CORE reason: Supported context-specific surface/extracellular activity; secondary to ER function. supported_by: - reference_id: PMID:11859136 supporting_text: Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading - term: id: GO:2000510 label: positive regulation of dendritic cell chemotaxis evidence_type: IMP original_reference_id: PMID:16140380 qualifier: involved_in review: summary: Calreticulin (cC1qR) mediates dendritic cell chemotaxis to C1q; a context-specific extracellular immune role, non-core. action: KEEP_AS_NON_CORE reason: Supported context-specific extracellular activity; secondary to ER function. supported_by: - reference_id: PMID:16140380 supporting_text: Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR - term: id: GO:0034504 label: protein localization to nucleus evidence_type: IDA original_reference_id: PMID:15998798 qualifier: involved_in review: summary: Linked to the calreticulin/calcineurin/MEF2C signaling cascade affecting nuclear localization of downstream factors; cytosolic moonlighting, non-core. action: KEEP_AS_NON_CORE reason: Part of the cytosolic Ca2+-signaling moonlighting; secondary to ER function. supported_by: - reference_id: PMID:15998798 supporting_text: Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade. - term: id: GO:0005509 label: calcium ion binding evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Sequence/orthology-transferred calcium ion binding consistent with the core conserved function. action: ACCEPT reason: Matches the well-supported core Ca2+-binding function. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0050821 label: protein stabilization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence/orthology-transferred protein stabilization consistent with the core chaperone role. action: ACCEPT reason: Matches the supported chaperone-mediated stabilization function. supported_by: - reference_id: PMID:17563366 supporting_text: CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated. - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:8666824 qualifier: enables review: summary: Binding to the TRIM21/Ro52 (an E3 ligase) autoantigen; a specific but non-core interaction. action: KEEP_AS_NON_CORE reason: Specific documented interaction (Ro/SS-A context); secondary to the ER chaperone role. supported_by: - reference_id: PMID:8666824 supporting_text: Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen. - term: id: GO:0044183 label: protein folding chaperone evidence_type: TAS original_reference_id: PMID:15474971 qualifier: enables review: summary: Protein folding chaperone is an accurate core molecular function for calreticulin. action: ACCEPT reason: Calreticulin is a bona fide molecular chaperone. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways. - term: id: GO:0003729 label: mRNA binding evidence_type: IDA original_reference_id: PMID:14726956 qualifier: enables review: summary: mRNA binding (p21 mRNA) reflects cytosolic moonlighting; non-core molecular function. action: KEEP_AS_NON_CORE reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role. supported_by: - reference_id: PMID:14726956 supporting_text: Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate - term: id: GO:0017148 label: negative regulation of translation evidence_type: TAS original_reference_id: PMID:12242300 qualifier: involved_in review: summary: Cytosolic calreticulin represses translation of C/EBP mRNAs; a moonlighting activity, non-core. action: KEEP_AS_NON_CORE reason: Documented cytosolic translational-repression moonlighting; secondary to the ER role. supported_by: - reference_id: PMID:12242300 supporting_text: Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins. - term: id: GO:0050821 label: protein stabilization evidence_type: TAS original_reference_id: PMID:10581245 qualifier: involved_in review: summary: Protein stabilization via in vitro chaperone activity (glycosylated and non-glycosylated substrates); consistent with the core chaperone role. action: ACCEPT reason: Supported chaperone-mediated stabilization function. supported_by: - reference_id: PMID:10581245 supporting_text: Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. - term: id: GO:0001849 label: complement component C1q complex binding evidence_type: TAS original_reference_id: PMID:15474971 qualifier: enables review: summary: C1q complex binding is a documented immune/extracellular function but non-core. action: KEEP_AS_NON_CORE reason: Specific supported interaction relevant to complement/clearance; secondary to the ER role. supported_by: - reference_id: PMID:15474971 supporting_text: The protein also plays an important role in autoimmunity and cancer. - term: id: GO:0002502 label: peptide antigen assembly with MHC class I protein complex evidence_type: ISS original_reference_id: PMID:11825569 qualifier: involved_in review: summary: MHC class I peptide antigen assembly is supported; CALR-null cells have impaired MHC I assembly. action: KEEP_AS_NON_CORE reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. supported_by: - reference_id: PMID:11825569 supporting_text: Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin - term: id: GO:0008270 label: zinc ion binding evidence_type: TAS original_reference_id: PMID:15474971 qualifier: enables review: summary: Zinc ion binding has been reported but is weakly supported relative to the well-characterized Ca2+-binding function; not a core function. action: MARK_AS_OVER_ANNOTATED reason: Minor/uncertain metal-binding property; not a credible core molecular function. - term: id: GO:0009986 label: cell surface evidence_type: TAS original_reference_id: PMID:15474971 qualifier: located_in review: summary: Cell-surface localization is real (eat-me signal) but non-core. action: KEEP_AS_NON_CORE reason: Documented surface exposure; secondary to ER function. supported_by: - reference_id: PMID:10358038 supporting_text: the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells - term: id: GO:0030246 label: carbohydrate binding evidence_type: TAS original_reference_id: PMID:15474971 qualifier: enables review: summary: Carbohydrate (monoglucosylated N-glycan) binding is a core lectin molecular function. action: ACCEPT reason: Underlies the lectin-chaperone activity of calreticulin. supported_by: - reference_id: PMID:15056662 supporting_text: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin - term: id: GO:0042824 label: MHC class I peptide loading complex evidence_type: ISS original_reference_id: PMID:11825569 qualifier: part_of review: summary: Calreticulin is a component of the MHC class I peptide loading complex. action: KEEP_AS_NON_CORE reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. supported_by: - reference_id: PMID:11825569 supporting_text: Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin - term: id: GO:0050766 label: positive regulation of phagocytosis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Surface calreticulin promotes phagocytosis (eat-me signal); a real but non-core role. action: KEEP_AS_NON_CORE reason: Documented immunogenic-cell-death/eat-me biology; secondary to ER function. - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:8107809 qualifier: involved_in review: summary: Derives from in vitro inhibition of nuclear hormone receptor activity via the KxFFKR DNA-binding-domain motif; a moonlighting effect rather than direct transcriptional regulation. action: MARK_AS_OVER_ANNOTATED reason: Calreticulin is not a transcription factor; the effect is indirect via receptor sequestration and is non-core. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0005178 label: integrin binding evidence_type: IPI original_reference_id: PMID:1911778 qualifier: enables review: summary: In vitro binding to the conserved KLGFFKR integrin alpha cytoplasmic-tail motif; a biochemically documented but cytosolic non-core interaction. action: KEEP_AS_NON_CORE reason: Specific documented binding; cytosolic and not the conserved ER function. supported_by: - reference_id: PMID:1911778 supporting_text: a highly conserved motif in the cytoplasmic domain adjacent to the transmembrane domain of the alpha subunit of integrins - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:8107809 qualifier: located_in review: summary: Nuclear localization linked to the steroid-receptor moonlighting reports; a minor non-core pool. action: KEEP_AS_NON_CORE reason: Minor nuclear pool tied to moonlighting; secondary to ER function. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:1911778 qualifier: located_in review: summary: Cytoplasmic localization supports cytosolic moonlighting functions; non-core. action: KEEP_AS_NON_CORE reason: Documented cytoplasmic pool; secondary to ER function. - term: id: GO:0033144 label: negative regulation of intracellular steroid hormone receptor signaling pathway evidence_type: IDA original_reference_id: PMID:8107809 qualifier: involved_in review: summary: In vitro inhibition of steroid receptor signaling via the KxFFKR motif; a documented but non-core moonlighting activity. action: KEEP_AS_NON_CORE reason: Specific documented effect on steroid-receptor signaling; secondary to the ER chaperone function. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0042921 label: nuclear receptor-mediated glucocorticoid signaling pathway evidence_type: TAS original_reference_id: PMID:8107809 qualifier: involved_in review: summary: Related to the glucocorticoid-receptor inhibition moonlighting role; non-core. action: KEEP_AS_NON_CORE reason: Documented GR-related effect; secondary to the ER function. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0045665 label: negative regulation of neuron differentiation evidence_type: IDA original_reference_id: PMID:8107809 qualifier: involved_in review: summary: Derives from inhibition of retinoic-acid/nuclear-receptor signaling in the same in vitro study; over-broad downstream effect. action: MARK_AS_OVER_ANNOTATED reason: Indirect downstream developmental effect of receptor inhibition; not a core function. - term: id: GO:0045892 label: negative regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:8107809 qualifier: involved_in review: summary: Indirect transcriptional effect via nuclear-receptor sequestration; over-broad. action: MARK_AS_OVER_ANNOTATED reason: Calreticulin is not a transcription factor; the effect is indirect and non-core. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0048387 label: negative regulation of retinoic acid receptor signaling pathway evidence_type: IDA original_reference_id: PMID:8107809 qualifier: involved_in review: summary: In vitro inhibition of retinoic-acid receptor signaling via the KxFFKR motif; documented but non-core moonlighting. action: KEEP_AS_NON_CORE reason: Specific documented effect on a nuclear receptor; secondary to the ER function. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IDA original_reference_id: PMID:1911778 qualifier: located_in review: summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; descriptive non-core localization. action: KEEP_AS_NON_CORE reason: Consistent with perinuclear ER; not a distinct functional compartment. - term: id: GO:0050681 label: nuclear androgen receptor binding evidence_type: IDA original_reference_id: PMID:8107809 qualifier: enables review: summary: Calreticulin binds the androgen receptor DNA-binding domain (KxFFKR motif) in vitro; a specific but non-core moonlighting interaction. action: KEEP_AS_NON_CORE reason: Specific documented binding underlying the steroid-receptor inhibition; secondary to the ER function. supported_by: - reference_id: PMID:8107809 supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: TAS original_reference_id: PMID:16130169 qualifier: involved_in review: summary: Apoptosis regulation is an over-broad downstream association from an apoptosis proteomics study. action: MARK_AS_OVER_ANNOTATED reason: Over-broad BP; not a direct calreticulin molecular function. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:16130169 qualifier: located_in review: summary: ER localization consistent with the core compartment. action: ACCEPT reason: Matches the established ER localization. - term: id: GO:0003677 label: DNA binding evidence_type: NAS original_reference_id: PMID:11149926 qualifier: enables review: summary: DNA binding is a non-authored-statement claim with weak support; not a credible core molecular function. action: MARK_AS_OVER_ANNOTATED reason: Poorly supported; calreticulin is not a bona fide DNA-binding protein. - term: id: GO:0005509 label: calcium ion binding evidence_type: TAS original_reference_id: PMID:11149926 qualifier: enables review: summary: Calcium ion binding is a core conserved molecular function. action: ACCEPT reason: Well-supported core Ca2+-binding function. supported_by: - reference_id: PMID:15474971 supporting_text: Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IDA original_reference_id: PMID:11149926 qualifier: located_in review: summary: Direct ER lumen localization consistent with the core compartment. action: ACCEPT reason: Reinforces the established ER-luminal localization. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:11149926 qualifier: located_in review: summary: A cytosolic pool supports the nuclear-export moonlighting role; non-core. action: KEEP_AS_NON_CORE reason: Documented cytosolic pool; secondary to ER function. - term: id: GO:0006611 label: protein export from nucleus evidence_type: IDA original_reference_id: PMID:11149926 qualifier: involved_in review: summary: Cytosolic calreticulin mediates nuclear export of the glucocorticoid receptor; a moonlighting activity, non-core. action: KEEP_AS_NON_CORE reason: Documented nuclear-export moonlighting; secondary to the ER chaperone role. supported_by: - reference_id: PMID:11149926 supporting_text: Calreticulin Is a receptor for nuclear export. - term: id: GO:0006874 label: intracellular calcium ion homeostasis evidence_type: TAS original_reference_id: PMID:11149926 qualifier: involved_in review: summary: Regulation of intracellular calcium homeostasis is a core biological process for calreticulin. action: ACCEPT reason: Calreticulin is the major ER Ca2+ store and regulates ER/intracellular Ca2+ handling. supported_by: - reference_id: PMID:15474971 supporting_text: The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: TAS original_reference_id: PMID:8107808 qualifier: involved_in review: summary: Broad transcription-regulation claim from the glucocorticoid-receptor modulation study; indirect and over-broad. action: MARK_AS_OVER_ANNOTATED reason: Calreticulin is not a transcription factor; the effect is indirect via receptor binding. supported_by: - reference_id: PMID:8107808 supporting_text: Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. - term: id: GO:0005509 label: calcium ion binding evidence_type: TAS original_reference_id: PMID:7841019 qualifier: enables review: summary: Calcium ion binding established in placental calreticulin characterization; core molecular function. action: ACCEPT reason: Supports the well-established core Ca2+-binding function. supported_by: - reference_id: PMID:7841019 supporting_text: 'Human placental calreticulin: purification, characterization and association with other proteins.' core_functions: - description: Lectin chaperone that binds monoglucosylated N-glycans on nascent glycoproteins in the ER lumen and, with ERp57 and cyclophilin B recruited via its P domain, promotes their folding and oligomeric assembly as part of the calnexin/calreticulin cycle. molecular_function: id: GO:0044183 label: protein folding chaperone directly_involved_in: - id: GO:0034975 label: protein folding in endoplasmic reticulum locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: file:human/CALR/CALR-uniprot.txt supporting_text: Calcium-binding chaperone that promotes folding, oligomeric - reference_id: PMID:17563366 supporting_text: calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor - description: Lectin that recognizes monoglucosylated N-glycans, providing the carbohydrate-binding specificity that underlies glycoprotein quality control and retention of incompletely folded clients. molecular_function: id: GO:0030246 label: carbohydrate binding directly_involved_in: - id: GO:0036503 label: ERAD pathway locations: - id: GO:0044322 label: endoplasmic reticulum quality control compartment supported_by: - reference_id: PMID:15056662 supporting_text: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin - description: High-capacity calcium-binding protein that buffers ER calcium and regulates intracellular calcium homeostasis and ER calcium storage capacity. molecular_function: id: GO:0005509 label: calcium ion binding directly_involved_in: - id: GO:0006874 label: intracellular calcium ion homeostasis locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: PMID:15474971 supporting_text: The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. proposed_new_terms: [] suggested_questions: - question: Which of calreticulin's reported cytosolic/nuclear moonlighting activities (nuclear export, integrin-tail binding, mRNA binding, steroid-receptor inhibition) reflect physiologically significant functions versus in vitro observations? experts: - Michalak M - Opas M - question: Should the neomorphic, ligand-independent MPL-binding/activating activity of exon 9 frameshift mutant calreticulin be captured by a dedicated gain-of-function term (e.g. a receptor-activating molecular function distinct from the wild-type lectin-chaperone activity), given that it is a disease-specific neofunction not shared by wild-type CALR and therefore not part of existing_annotations? experts: - Mullally A - Elf SE suggested_experiments: - hypothesis: Surface-exposed calreticulin functions as a pro-phagocytic eat-me signal independently of its ER chaperone activity. description: Compare phagocytic uptake of cells displaying defined amounts of surface calreticulin (via controlled translocation or recombinant coating) with and without blocking antibodies and LRP1 perturbation, while monitoring ER chaperone status. experiment_type: phagocytosis assay with surface-calreticulin manipulation - hypothesis: The high-capacity ER Ca2+-buffering function of wild-type calreticulin is the specific activity whose loss in type 1 exon 9 mutants drives IRE1α/XBP1-dependent survival, distinguishing type 1 from type 2 mutant biology. description: In isogenic cells expressing wild-type, type 1, or type 2 CALR, quantify ER luminal Ca2+ and IRE1α/XBP1 activation, then test whether restoring Ca2+-binding capacity (e.g. C-domain acidic-residue add-back) or IRE1α inhibition selectively rescues or kills type 1 mutant cells. experiment_type: ER calcium and UPR profiling in isogenic CALR-mutant cell lines references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10358038 title: Calreticulin is expressed on the cell surface of activated human peripheral blood T lymphocytes in association with major histocompatibility complex class I molecules. findings: - statement: Calreticulin is an ER-resident chaperone that is also displayed on the surface of activated T cells in association with MHC class I. supporting_text: the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells reference_section_type: ABSTRACT - id: PMID:10581245 title: Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. findings: - statement: Calreticulin acts as a molecular chaperone in vitro for both glycosylated and non-glycosylated substrates. supporting_text: Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. reference_section_type: TITLE - id: PMID:10605026 title: HLA-F is a predominantly empty, intracellular, TAP-associated MHC class Ib protein with a restricted expression pattern. findings: [] - id: PMID:11149926 title: Calreticulin Is a receptor for nuclear export. findings: - statement: Cytosolic calreticulin can act as a nuclear export receptor for the glucocorticoid receptor. supporting_text: Calreticulin Is a receptor for nuclear export. reference_section_type: TITLE - id: PMID:11825569 title: Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. findings: - statement: Cells lacking calreticulin have impaired MHC class I assembly and antigen presentation. supporting_text: Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin reference_section_type: TITLE - id: PMID:11859136 title: Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading. findings: [] - id: PMID:12242300 title: Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins. findings: [] - id: PMID:14726956 title: Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate. findings: [] - id: PMID:15056662 title: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin independently of their assembly status. findings: - statement: Calreticulin binds MHC class I molecules in a monoglucosylated N-glycan-dependent manner. supporting_text: Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin reference_section_type: TITLE - id: PMID:15474971 title: Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum. findings: - statement: Calreticulin is a Ca2+-binding ER chaperone involved in calcium homeostasis, ER calcium storage, and secretory-pathway quality control. supporting_text: The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. reference_section_type: ABSTRACT - id: PMID:15896298 title: In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. findings: [] - id: PMID:15998798 title: Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade. findings: [] - id: PMID:16130169 title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis. findings: [] - id: PMID:16140380 title: Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR. findings: [] - id: PMID:16502470 title: 'Human colostrum: identification of minor proteins in the aqueous phase by proteomics.' findings: [] - id: PMID:17055437 title: Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing. findings: [] - id: PMID:17215244 title: Purification and identification of G protein-coupled receptor protein complexes under native conditions. findings: [] - id: PMID:17563366 title: Calreticulin and Hsp90 stabilize the human insulin receptor and promote its mobility in the endoplasmic reticulum. findings: - statement: Calreticulin controls early maturation and stability of the human insulin receptor in the ER. supporting_text: both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER reference_section_type: ABSTRACT - id: PMID:17916189 title: Identification of calreticulin as a ligand of GABARAP by phage display screening of a peptide library. findings: [] - id: PMID:18177377 title: The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with MBL through the binding site for MBL-associated serine proteases. findings: [] - id: PMID:19154346 title: Structural framework of the GABARAP-calreticulin interface--implications for substrate binding to endoplasmic reticulum chaperones. findings: [] - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: [] - id: PMID:21263072 title: Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules. findings: [] - id: PMID:21423176 title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. findings: [] - id: PMID:21590275 title: Calreticulin-2 is localized in the lumen of the endoplasmic reticulum but is not a Ca2+ -binding protein. findings: [] - id: PMID:21630459 title: Proteomic characterization of the human sperm nucleus. findings: [] - id: PMID:21705382 title: Characterization of unique signature sequences in the divergent maternal protein Bcl2l10. findings: [] - id: PMID:21900206 title: A directed protein interaction network for investigating intracellular signal transduction. findings: [] - id: PMID:22013210 title: 'The unfolded protein response: integrating stress signals through the stress sensor IRE1α.' findings: [] - id: PMID:22377355 title: Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells. findings: [] - id: PMID:22572157 title: Sensitive detection of idiotypic platelet-reactive alloantibodies by an electrical protein chip. findings: [] - id: PMID:22658674 title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. findings: [] - id: PMID:23011799 title: ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. findings: [] - id: PMID:23395171 title: Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. findings: [] - id: PMID:24325356 title: Somatic mutations of calreticulin in myeloproliferative neoplasms. full_text_unavailable: true findings: - statement: Somatic +1 frameshift insertions/deletions in CALR exon 9 are recurrent driver mutations in essential thrombocythemia and primary myelofibrosis, are mutually exclusive with JAK2 and MPL mutations, and generate a novel mutant C-terminal peptide; these are neomorphic disease mutations rather than a function of wild-type calreticulin. - id: PMID:24325359 title: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. full_text_unavailable: true findings: - statement: CALR exon 9 +1 base-pair frameshift mutations are found in the majority of JAK2/MPL-nonmutated myeloproliferative neoplasms, arise in hematopoietic stem/progenitor cells as an initiating lesion, and produce a mutant calreticulin with a novel C-terminus that removes the normal Ca2+-binding tail and KDEL motif. - id: PMID:25241761 title: Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network. findings: [] - id: PMID:25277244 title: The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets. findings: [] - id: PMID:26514267 title: Protein interactome mining defines melatonin MT1 receptors as integral component of presynaptic protein complexes of neurons. findings: [] - id: PMID:27177927 title: Calreticulin-mutant proteins induce megakaryocytic signaling to transform hematopoietic cells and undergo accelerated degradation and Golgi-mediated secretion. full_text_unavailable: true findings: - statement: Mutant calreticulin drives megakaryocytic transformation through the thrombopoietin receptor MPL, producing constitutive STAT3/STAT5, ERK1/2 and AKT activation and cytokine-independent growth; the mutant protein undergoes accelerated degradation and Golgi-mediated secretion, distinguishing the oncogenic neomorphic activity from the wild-type ER chaperone function. - id: PMID:28298427 title: Systematic protein-protein interaction mapping for clinically relevant human GPCRs. findings: [] - id: PMID:30108113 title: Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer. findings: [] - id: PMID:30188326 title: Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:35405004 title: Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms. full_text_unavailable: true findings: - statement: Type 1 calreticulin mutants lose more acidic Ca2+-binding residues than type 2 mutants, directly impairing Ca2+ binding and depleting ER Ca2+, which selectively activates the IRE1α/XBP1 arm of the unfolded protein response; this mechanistically links calreticulin's high-capacity ER Ca2+-buffering function to mutation-type-specific oncogenic signaling. - id: PMID:35948544 title: Molecular basis of MHC I quality control in the peptide loading complex. findings: - statement: Calreticulin is a central chaperone of the MHC class I peptide loading complex, engulfing the monoglucosylated MHC I glycan and coupling epitope selection to glycan processing. supporting_text: peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan reference_section_type: ABSTRACT - id: PMID:36417879 title: Calreticulin mutations affect its chaperone function and perturb the glycoproteome. findings: - statement: Disease-associated calreticulin mutations impair its chaperone function and broadly perturb the cellular glycoproteome. supporting_text: Calreticulin mutations affect its chaperone function and perturb the glycoproteome. reference_section_type: TITLE - id: PMID:7841019 title: 'Human placental calreticulin: purification, characterization and association with other proteins.' findings: [] - id: PMID:8107808 title: Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. findings: [] - id: PMID:8107809 title: Inhibition of nuclear hormone receptor activity by calreticulin. findings: - statement: Calreticulin binds the DNA-binding domain of nuclear hormone receptors and inhibits their transcriptional activity in vitro. supporting_text: Inhibition of nuclear hormone receptor activity by calreticulin. reference_section_type: TITLE - id: PMID:8418194 title: The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. findings: - statement: Calreticulin is a major constituent of the lytic granules of cytolytic T lymphocytes. supporting_text: The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. reference_section_type: TITLE - id: PMID:8666824 title: Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen. findings: [] - id: PMID:9640257 title: Calreticulin associates with non-HLA-A,-B class I proteins in the human choriocarcinoma cell lines JEG-3 and BeWo. findings: [] - id: PMID:9922153 title: Evidence that C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin and interferes with complement activation. findings: - statement: C1q binds specifically to calreticulin, supporting calreticulin's role as a C1q-binding protein relevant to complement. supporting_text: C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin reference_section_type: TITLE - id: PMID:1911778 title: In vitro interaction of a polypeptide homologous to human Ro/SS-A antigen (calreticulin) with a highly conserved amino acid sequence in the cytoplasmic domain of integrin alpha subunits. findings: - statement: Calreticulin binds the conserved KLGFFKR motif in the cytoplasmic tail of integrin alpha subunits in vitro. supporting_text: a highly conserved motif in the cytoplasmic domain adjacent to the transmembrane domain of the alpha subunit of integrins reference_section_type: ABSTRACT - id: Reactome:R-HSA-1791082 title: Expression of Calreticulin findings: [] - id: Reactome:R-HSA-2247514 title: SCARF1:ligand is endocytosed findings: [] - id: Reactome:R-HSA-2507854 title: MSR1:ligand (SCARA1:ligand, SR-A:ligand) is endocytosed findings: [] - id: Reactome:R-HSA-535717 title: Binding of calnexin/calreticulin to the unfolded protein findings: [] - id: Reactome:R-HSA-548890 title: Removal of the third glucose by glucosidase II and release from the chaperone findings: [] - id: Reactome:R-HSA-8863858 title: SEC22B, CALR, STX4, TAP and TAPBP bind findings: [] - id: Reactome:R-HSA-8863914 title: Transport of SEC22B, TAP and PLC from ER to ERGIC findings: [] - id: Reactome:R-HSA-8951499 title: Loading of antigenic peptides on to class I MHC findings: [] - id: Reactome:R-HSA-8951595 title: CALR, TAP, TAPBP dissociate from SEC22B:STX4 findings: [] - id: Reactome:R-HSA-901047 title: Binding of ERp57 findings: [] - id: Reactome:R-HSA-983142 title: Formation of peptide loading complex (PLC) findings: [] - id: Reactome:R-HSA-983161 title: Dissociation of the Antigenic peptide:MHC:B2M peptide loading complex findings: [] - id: file:human/CALR/CALR-uniprot.txt title: CALR UniProtKB record (P27797) findings: [] - id: file:human/CALR/CALR-notes.md title: Manual CALR curation notes findings: []