Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Protein folding is a core biological process for calreticulin in the calnexin/calreticulin cycle. Reason: Phylogenetic transfer agrees with extensive evidence that calreticulin assists folding of nascent glycoproteins in the ER. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: The calnexin/calreticulin cycle triages terminally misfolded glycoproteins toward ER-associated degradation, supporting participation in the ERAD pathway. Reason: Quality-control retention and triage of non-native clients is an established core role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Calcium ion binding is a core conserved molecular function; calreticulin is the major high-capacity ER Ca2+-binding protein. Reason: Well-supported by biochemistry and the conserved calreticulin-family Ca2+-binding domains. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005509 calcium ion binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic calcium ion binding annotation duplicates the core conserved molecular function. Reason: Consistent with experimental and phylogenetic evidence for Ca2+ binding. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005737 cytoplasm	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: A cytoplasmic pool of calreticulin exists (cytosolic moonlighting), but it is non-core relative to the ER-luminal chaperone function. Reason: Cytosolic calreticulin is documented for moonlighting roles, but the bulk functional protein is ER-luminal. Supporting Evidence: file:human/CALR/CALR-uniprot.txt cytosol and extracellular matrix (PubMed:10358038)
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: ER localization is the core compartment for calreticulin. Reason: Calreticulin is a resident ER-luminal protein. Supporting Evidence: file:human/CALR/CALR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000120	ACCEPT	Summary: ER lumen is the precise core localization of this soluble chaperone. Reason: Calreticulin bears a KDEL retention signal and resides in the ER lumen. Supporting Evidence: file:human/CALR/CALR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A cytosolic pool supports moonlighting functions but is non-core. Reason: Cytosolic calreticulin is documented but secondary to the ER chaperone role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt cytosol and extracellular matrix (PubMed:10358038)
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: Electronic protein folding annotation duplicates the core folding role. Reason: Consistent with experimental and phylogenetic evidence for chaperone-assisted folding. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0009986 cell surface	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Cell-surface calreticulin is real (eat-me signal, T-cell surface) but non-core relative to ER function. Reason: Surface exposure is a documented secondary localization linked to phagocytic clearance and immune signaling. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0012505 endomembrane system	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Endomembrane system is correct but uninformatively broad; the precise compartment is the ER lumen. Reason: Subsumed by the more specific ER lumen annotation.
GO:0033018 sarcoplasmic reticulum lumen	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Sarcoplasmic reticulum lumen is the muscle-cell equivalent of the ER lumen; a valid specialized localization but non-core. Reason: Reflects the ER/SR continuum in muscle; not distinct from the core ER-luminal role.
GO:0044194 cytolytic granule	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Calreticulin is a major constituent of cytolytic (lytic) granules of CTLs; a real but specialized non-core localization. Reason: Documented localization in lytic granules, secondary to the ER chaperone function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Cytolytic granule
GO:0060473 cortical granule	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cortical granule localization (oocytes) is an ortholog-supported specialized pool linked to the block to polyspermy; non-core. Reason: Documented in oocyte cortical granules by similarity; secondary to the ER role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Cortical granule
GO:0005515 protein binding	IPI PMID:15896298 In cerebrospinal fluid ER chaperones ERp57 and calreticulin ...	MARK AS OVER ANNOTATED	Summary: Bare protein binding (ERp57/beta-amyloid in CSF study) is uninformative. Reason: Per guidelines, generic protein binding does not convey calreticulin function.
GO:0005515 protein binding	IPI PMID:17055437 Redox regulation facilitates optimal peptide selection by MH...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin's role in redox-regulated MHC I peptide selection, but bare protein binding is uninformative. Reason: The functional content is MHC I peptide loading, captured by PLC terms; generic protein binding adds nothing.
GO:0005515 protein binding	IPI PMID:17215244 Purification and identification of G protein-coupled recepto...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a GPCR-complex study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:18177377 The chaperone and potential mannan-binding lectin (MBL) co-r...	MARK AS OVER ANNOTATED	Summary: This reflects the calreticulin-MBL interaction (cC1qR/MBL co-receptor), but bare protein binding is uninformative. Reason: The MBL/innate-immune interaction is a non-core extracellular role; generic protein binding does not capture it.
GO:0005515 protein binding	IPI PMID:19154346 Structural framework of the GABARAP-calreticulin interface--...	MARK AS OVER ANNOTATED	Summary: Generic protein binding (GABARAP-calreticulin interface) is uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:20562859 Network organization of the human autophagy system.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an autophagy-network interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:21900206 A directed protein interaction network for investigating int...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a directed signal-transduction interaction network; uninformative. Reason: High-throughput interaction; bare protein binding adds no functional information.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a proximity-ligation pathway profiling study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:25277244 The functional landscape of Hsp27 reveals new cellular proce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an Hsp27 functional-landscape study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:26514267 Protein interactome mining defines melatonin MT1 receptors a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a melatonin MT1 presynaptic interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:28298427 Systematic protein-protein interaction mapping for clinicall...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a GPCR interaction-mapping study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:30108113 Comprehensive evaluation of coding region point mutations in...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a colorectal-cancer mutation study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a reference binary interactome; uninformative. Reason: High-throughput interactome hit; bare protein binding adds no functional information.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a neurodegenerative-disease interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:36417879 Calreticulin mutations affect its chaperone function and per...	MARK AS OVER ANNOTATED	Summary: This study shows mutant calreticulin perturbs the glycoproteome, but bare protein binding is uninformative. Reason: The functional content is glycoprotein chaperoning; generic protein binding does not capture it. Supporting Evidence: PMID:36417879 Calreticulin mutations affect its chaperone function and perturb the glycoproteome.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Acrosomal vesicle localization is an ortholog-transferred specialized pool; non-core and weakly supported for human. Reason: Ortholog phenotype/localization transfer; not part of the core ER function.
GO:0002502 peptide antigen assembly with MHC class I protein complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: MHC class I peptide antigen assembly is a well-supported specialized role of calreticulin in the peptide loading complex. Reason: This is a specialized application of the lectin-chaperone function; supported directly (see IDA from PMID:35948544) but secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0003729 mRNA binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: mRNA binding reflects cytosolic moonlighting (e.g. p21, C/EBP mRNAs); documented but non-core for an ER lectin chaperone. Reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role.
GO:0005506 iron ion binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Iron ion binding is an ortholog-transferred metal-binding claim with weak support; not a credible core function. Reason: Poorly supported metal-binding inference; calreticulin's characterized metal ligand is Ca2+.
GO:0005576 extracellular region	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A secreted/extracellular pool of calreticulin exists but is non-core. Reason: Documented extracellular/secreted localization, secondary to ER function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Secreted, extracellular space,
GO:0005635 nuclear envelope	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Nuclear envelope localization likely reflects continuity with the ER and a minor nuclear-envelope pool; non-core. Reason: A minor localization, partly reflecting ER/nuclear-envelope continuity.
GO:0005739 mitochondrion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Mitochondrial localization is an ortholog-transferred over-call for a soluble ER-luminal chaperone. Reason: Not supported by direct human evidence; an ER protein is unlikely to be a genuine mitochondrial resident.
GO:0005790 smooth endoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Smooth ER is a sub-compartment of the broader ER localization; subsumed by the core ER annotation. Reason: A specific ER sub-compartment; not distinct from the core ER-luminal role.
GO:0007283 spermatogenesis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Spermatogenesis is an ortholog-derived phenotype-transfer over-annotation. Reason: Phenotype transfer, not a direct molecular function of human calreticulin.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to xenobiotic stimulus is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0009897 external side of plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: External side of the plasma membrane corresponds to surface-exposed (eat-me) calreticulin; real but non-core. Reason: Surface exposure is documented; secondary to the ER chaperone role. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of gene expression is an over-broad downstream/ortholog-transferred effect. Reason: Over-broad BP not reflecting a direct calreticulin molecular activity.
GO:0016529 sarcoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Sarcoplasmic reticulum is the muscle ER equivalent; a valid specialized localization but non-core. Reason: Reflects ER/SR continuum in muscle; not distinct from the core ER role.
GO:0030246 carbohydrate binding	IEA GO_REF:0000107	ACCEPT	Summary: Carbohydrate (monoglucosylated N-glycan) binding is a core molecular function underlying the lectin-chaperone activity. Reason: Calreticulin is a lectin that binds monoglucosylated glycans on glycoprotein clients. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0031012 extracellular matrix	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Extracellular matrix localization reflects the secreted/extracellular pool; non-core. Reason: Documented extracellular/matrix pool, secondary to ER function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Secreted, extracellular space,
GO:0032355 response to estradiol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to estradiol is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0032991 protein-containing complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic protein-containing complex membership is uninformative. Reason: Too general; specific complexes (PLC) are captured elsewhere.
GO:0033574 response to testosterone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to testosterone is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0034504 protein localization to nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Protein localization to nucleus relates to the cytosolic nuclear-export moonlighting role; non-core. Reason: Linked to the documented nuclear-export receptor activity; secondary to ER function.
GO:0042277 peptide binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Peptide binding is consistent with calreticulin's chaperone interactions (e.g. in MHC I peptide loading) but is a broad MF. Reason: Generic peptide binding partially reflects the chaperone/PLC role; retain as non-core rather than core.
GO:0042562 hormone binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Hormone binding is a weakly supported ortholog-transferred MF. Reason: Not a credible core molecular function; likely derived from steroid-receptor moonlighting reports.
GO:0042824 MHC class I peptide loading complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Calreticulin is a bona fide component of the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to the general glycoprotein-folding core function. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0044322 endoplasmic reticulum quality control compartment	IEA GO_REF:0000107	ACCEPT	Summary: Localization to the ER quality control compartment is consistent with calreticulin's retention/triage role. Reason: Directly aligned with the core ER quality-control function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0045787 positive regulation of cell cycle	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of cell cycle is an over-broad downstream/ortholog-transferred effect. Reason: Over-broad BP not reflecting a direct calreticulin activity.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; non-core descriptive localization. Reason: Consistent with perinuclear ER; not a distinct functional compartment.
GO:0050766 positive regulation of phagocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Surface calreticulin acts as an eat-me signal promoting phagocytosis; a real but non-core role. Reason: Well-documented immunogenic-cell-death/eat-me biology; secondary to the ER chaperone function.
GO:0050821 protein stabilization	IEA GO_REF:0000107	ACCEPT	Summary: Protein stabilization captures calreticulin's chaperone-mediated stabilization of folding clients. Reason: Consistent with experimental evidence (e.g. insulin receptor stabilization) and the core chaperone role. Supporting Evidence: PMID:17563366 calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor
GO:0055007 cardiac muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A cardiac developmental role is documented from calreticulin-knockout mice; an ortholog-supported developmental effect rather than the core human function. Reason: CALR-null mice show essential cardiac developmental defects; retain as non-core developmental role. Supporting Evidence: PMID:15474971 Studies on calreticulin knockout mice indicate that the protein is essential in early cardiac development.
GO:0071257 cellular response to electrical stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to electrical stimulus is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0071285 cellular response to lithium ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to lithium ion is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0090398 cellular senescence	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular senescence is a downstream/ortholog-transferred effect (cf. p21 translation control); over-broad. Reason: Over-broad downstream BP, not a direct calreticulin function.
GO:0098586 cellular response to virus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to virus is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0098794 postsynapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Postsynapse localization/activity is an ortholog-transferred neuronal over-call for an ER chaperone. Reason: Not supported by direct human evidence; not a core function.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Glutamatergic synapse activity is an ortholog-transferred neuronal over-call. Reason: Not supported by direct human evidence; not a core function.
GO:1901652 response to peptide	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to peptide is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:1903416 response to glycoside	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to glycoside is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:1904614 response to biphenyl	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to biphenyl is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0005783 endoplasmic reticulum	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	ACCEPT	Summary: Calreticulin is active in the ER as part of the MHC I peptide loading complex; core compartment of action. Reason: Direct evidence of calreticulin acting in the ER within the PLC. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: In the PLC, calreticulin bridges the MHC I glycan to the editing machinery, consistent with an adaptor/scaffolding molecular function. Reason: Supported within the PLC context; a specialized adaptor role secondary to the lectin-chaperone core function. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0042824 MHC class I peptide loading complex	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: Direct structural evidence places calreticulin in the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC)
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005788 endoplasmic reticulum lumen	EXP PMID:10358038 Calreticulin is expressed on the cell surface of activated h...	ACCEPT	Summary: Experimental evidence confirms calreticulin in the ER lumen. Reason: Direct support for the core ER-luminal localization. Supporting Evidence: PMID:10358038 Calreticulin is an endoplasmic reticulum resident molecule
GO:0009986 cell surface	EXP PMID:10358038 Calreticulin is expressed on the cell surface of activated h...	KEEP AS NON CORE	Summary: Experimental evidence shows surface calreticulin on activated T cells; a real but non-core localization. Reason: Direct demonstration of surface exposure; secondary to the ER role. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0033018 sarcoplasmic reticulum lumen	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence/orthology-transferred SR lumen localization (muscle ER equivalent); non-core. Reason: Reflects the ER/SR continuum; not distinct from the core ER role.
GO:0044194 cytolytic granule	EXP PMID:8418194 The calcium-binding protein calreticulin is a major constitu...	KEEP AS NON CORE	Summary: Calreticulin is experimentally shown to be a major constituent of CTL lytic granules; specialized non-core localization. Reason: Direct evidence for lytic-granule localization; secondary to the ER function. Supporting Evidence: PMID:8418194 The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes.
GO:0005509 calcium ion binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Calcium ion binding is a core molecular function; calreticulin regulates ER Ca2+ storage. Reason: Well-supported synthesis source for the core Ca2+-binding function. Supporting Evidence: PMID:15474971 The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity.
GO:0002502 peptide antigen assembly with MHC class I protein complex	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: Direct evidence supports calreticulin's involvement in MHC class I peptide antigen assembly. Reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0006457 protein folding	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Direct evidence supports calreticulin's role in folding/maturation of a glycoprotein client (insulin receptor). Reason: Core biological process supported by direct experimental data. Supporting Evidence: PMID:17563366 both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER
GO:0044183 protein folding chaperone	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Protein folding chaperone is an accurate core molecular function for calreticulin. Reason: Calreticulin is a bona fide molecular chaperone for glycoprotein clients. Supporting Evidence: PMID:17563366 calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor
GO:0050821 protein stabilization	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Calreticulin stabilizes folding clients (insulin receptor variant); core chaperone-related process. Reason: Directly supported stabilization of a misfolded client. Supporting Evidence: PMID:17563366 CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated.
GO:0051604 protein maturation	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Calreticulin contributes to glycoprotein maturation in the ER; consistent with the core chaperone function. Reason: Directly supported role in early client maturation. Supporting Evidence: PMID:17563366 both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-8863914	ACCEPT	Summary: As a soluble ER-luminal protein, calreticulin functions on the luminal side of the ER membrane. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-8951499	ACCEPT	Summary: Luminal-side ER membrane localization (MHC I peptide loading pathway) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-983142	ACCEPT	Summary: Luminal-side ER membrane localization (PLC formation) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-983161	ACCEPT	Summary: Luminal-side ER membrane localization (PLC dissociation) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0005840 ribosome	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: Ribosome association reflects cytosolic calreticulin in mRNA-translation regulation (p21); a moonlighting context, non-core. Reason: Linked to cytosolic translational-control moonlighting; not the core ER localization.
GO:0001849 complement component C1q complex binding	IPI PMID:9922153 Evidence that C1q binds specifically to CH2-like immunoglobu...	KEEP AS NON CORE	Summary: Calreticulin (cC1qR) binds the C1q complex; a documented immune/extracellular molecular function but non-core. Reason: Specific, supported C1q-binding activity relevant to complement and apoptotic-cell clearance; secondary to the ER chaperone role. Supporting Evidence: PMID:9922153 C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin
GO:0005049 nuclear export signal receptor activity	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: Cytosolic calreticulin was reported to act as a nuclear export receptor for the glucocorticoid receptor; a moonlighting activity, non-core. Reason: Documented but specialized cytosolic moonlighting function distinct from the ER chaperone role. Supporting Evidence: PMID:11149926 Calreticulin Is a receptor for nuclear export.
GO:0005515 protein binding	IPI PMID:17916189 Identification of calreticulin as a ligand of GABARAP by pha...	MARK AS OVER ANNOTATED	Summary: Generic protein binding (GABARAP ligand identification); uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005509 calcium ion binding	IMP PMID:21705382 Characterization of unique signature sequences in the diverg...	ACCEPT	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. 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. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0045787 positive regulation of cell cycle	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Cell-cycle regulation via competition with CUGBP1 for p21 translation is a cytosolic moonlighting effect; over-broad as a core BP. Reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function.
GO:0060473 cortical granule	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence/orthology-transferred cortical granule localization (oocytes); non-core specialized pool. Reason: Documented by similarity; secondary to ER function.
GO:0005783 endoplasmic reticulum	IDA PMID:30188326 Deletion of Tmtc4 activates the unfolded protein response an...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0042824 MHC class I peptide loading complex	IDA PMID:21263072 Distinct functions for the glycans of tapasin and heavy chai...	KEEP AS NON CORE	Summary: Direct evidence supports calreticulin as a PLC component (glycan-dependent MHC I assembly). Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:21263072 Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules
GO:0005515 protein binding	IPI PMID:10605026 HLA-F is a predominantly empty, intracellular, TAP-associate...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin association with HLA-F (an MHC Ib client), but bare protein binding is uninformative. Reason: The functional content is MHC I chaperoning; generic protein binding does not capture it.
GO:0005515 protein binding	IPI PMID:9640257 Calreticulin associates with non-HLA-A,-B class I proteins i...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin association with non-classical MHC class I proteins, but bare protein binding is uninformative. Reason: The functional content is MHC I chaperoning; generic protein binding does not capture it.
GO:0005509 calcium ion binding	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	ACCEPT	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. 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. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005635 nuclear envelope	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	KEEP AS NON CORE	Summary: Nuclear envelope localization reflects ER/nuclear-envelope continuity; non-core. Reason: A minor localization partly reflecting ER continuity.
GO:0005788 endoplasmic reticulum lumen	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	ACCEPT	Summary: Direct ER lumen localization consistent with the core compartment. Reason: Reinforces the established ER-luminal localization.
GO:0005576 extracellular region	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular/secreted calreticulin affecting cell migration; non-core extracellular role. Reason: Documented extracellular activity; secondary to ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:0010595 positive regulation of endothelial cell migration	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular calreticulin promotes endothelial cell migration; a context-specific non-core role. Reason: Supported context-specific extracellular activity, not the core ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:1901164 negative regulation of trophoblast cell migration	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular calreticulin inhibits trophoblast migration; a context-specific non-core role. Reason: Supported context-specific extracellular activity, not the core ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:0008284 positive regulation of cell population proliferation	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Proliferation regulation via p21 translation control is a cytosolic moonlighting effect; over-broad as a core BP. Reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function.
GO:0017148 negative regulation of translation	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: Cytosolic calreticulin can repress translation of specific mRNAs (p21); a moonlighting activity, non-core. Reason: Documented cytosolic translational-control moonlighting; secondary to the ER role. Supporting Evidence: PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate
GO:0090398 cellular senescence	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Senescence is a downstream effect of cytosolic p21 translation control; over-broad. Reason: Downstream/indirect effect, not a direct calreticulin function.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8863858	KEEP AS NON CORE	Summary: ERGIC membrane localization reflects trafficking of calreticulin-containing complexes; a minor non-core localization. Reason: Transient trafficking compartment localization; secondary to ER-luminal residence.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8863914	KEEP AS NON CORE	Summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. Reason: Transient trafficking compartment; secondary to ER residence.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8951595	KEEP AS NON CORE	Summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. Reason: Transient trafficking compartment; secondary to ER residence.
GO:0034975 protein folding in endoplasmic reticulum	TAS PMID:22013210 The unfolded protein response: integrating stress signals th...	ACCEPT	Summary: Protein folding in the ER is the precise core biological process for calreticulin. Reason: Most accurate BP term for calreticulin's chaperone activity. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0016020 membrane	IDA PMID:22572157 Sensitive detection of idiotypic platelet-reactive alloantib...	MARK AS OVER ANNOTATED	Summary: Generic membrane localization is uninformatively broad. Reason: Subsumed by more specific ER/cell-surface localizations.
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	KEEP AS NON CORE	Summary: Focal adhesion localization from a high-throughput proteome; consistent with the integrin-tail interaction but non-core. Reason: Plausible given integrin-tail binding, but high-throughput and secondary to ER function.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Generic membrane from an NK-cell membrane proteome; uninformatively broad. Reason: Subsumed by more specific localizations.
GO:0005576 extracellular region	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	KEEP AS NON CORE	Summary: Extracellular detection in colostrum proteomics; non-core secreted pool. Reason: Documented secreted/extracellular detection; secondary to ER function.
GO:0005515 protein binding	IPI PMID:15056662 Major histocompatibility complex class I molecules expressed...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin binding monoglucosylated MHC I glycans, more informatively captured as carbohydrate binding than bare protein binding. Reason: The functional content is glycan-dependent MHC I binding, captured by carbohydrate-binding/PLC terms; generic protein binding adds nothing. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Nuclear detection in a sperm-nucleus proteome; non-core moonlighting/contaminant-prone localization. Reason: A minor nuclear pool consistent with nuclear moonlighting reports; secondary to ER function.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: RNA binding from a global mRNA-interactome capture; not a credible core molecular function. Reason: High-throughput RNA-capture; not a genuine primary function for an ER lectin chaperone.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Exosome detection in parotid-gland proteomics; non-core, likely incidental. Reason: High-throughput exosome detection; secondary to ER function.
GO:0005783 endoplasmic reticulum	IDA PMID:23395171 Tmem64 modulates calcium signaling during RANKL-mediated ost...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005783 endoplasmic reticulum	IDA PMID:23011799 ORMDL3 is an inducible lung epithelial gene regulating metal...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2247514	KEEP AS NON CORE	Summary: Extracellular calreticulin in scavenger-receptor (SCARF1) clearance pathway; non-core. Reason: Reflects extracellular eat-me/clearance biology; secondary to ER function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2507854	KEEP AS NON CORE	Summary: Extracellular calreticulin in scavenger-receptor (MSR1) clearance pathway; non-core. Reason: Reflects extracellular eat-me/clearance biology; secondary to ER function.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-8951595	KEEP AS NON CORE	Summary: Phagocytic vesicle membrane localization in cross-presentation; non-core specialized localization. Reason: Specialized immune-pathway localization; secondary to ER function.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2247514	KEEP AS NON CORE	Summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. Reason: Reflects extracellular/endocytic clearance biology; secondary to ER function.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2507854	KEEP AS NON CORE	Summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. Reason: Reflects extracellular/endocytic clearance biology; secondary to ER function.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-1791082	ACCEPT	Summary: ER lumen localization (calreticulin expression); accurate core compartment. Reason: Consistent with the core ER-luminal localization.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-535717	ACCEPT	Summary: ER lumen localization for the chaperone-client binding step; accurate. Reason: Consistent with the core ER-luminal localization and function.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-548890	ACCEPT	Summary: ER lumen localization for the glucosidase II/release step; accurate. Reason: Consistent with the core ER-luminal localization and the CNX/CRT cycle.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-901047	ACCEPT	Summary: ER lumen localization for ERp57 binding; accurate and functionally central. Reason: Consistent with calreticulin's ERp57-recruiting role in the ER lumen.
GO:1900026 positive regulation of substrate adhesion-dependent cell spreading	IMP PMID:11859136 Cooperation of C1q receptors and integrins in C1q-mediated e...	KEEP AS NON CORE	Summary: Calreticulin (with C1q receptors/integrins) promotes endothelial cell adhesion/spreading; a context-specific extracellular role, non-core. Reason: Supported context-specific surface/extracellular activity; secondary to ER function. Supporting Evidence: PMID:11859136 Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading
GO:2000510 positive regulation of dendritic cell chemotaxis	IMP PMID:16140380 Chemotaxis of human monocyte-derived dendritic cells to comp...	KEEP AS NON CORE	Summary: Calreticulin (cC1qR) mediates dendritic cell chemotaxis to C1q; a context-specific extracellular immune role, non-core. Reason: Supported context-specific extracellular activity; secondary to ER function. Supporting Evidence: PMID:16140380 Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR
GO:0034504 protein localization to nucleus	IDA PMID:15998798 Calreticulin signals upstream of calcineurin and MEF2C in a ...	KEEP AS NON CORE	Summary: Linked to the calreticulin/calcineurin/MEF2C signaling cascade affecting nuclear localization of downstream factors; cytosolic moonlighting, non-core. Reason: Part of the cytosolic Ca2+-signaling moonlighting; secondary to ER function. Supporting Evidence: PMID:15998798 Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade.
GO:0005509 calcium ion binding	ISS GO_REF:0000024	ACCEPT	Summary: Sequence/orthology-transferred calcium ion binding consistent with the core conserved function. Reason: Matches the well-supported core Ca2+-binding function. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0050821 protein stabilization	ISS GO_REF:0000024	ACCEPT	Summary: Sequence/orthology-transferred protein stabilization consistent with the core chaperone role. Reason: Matches the supported chaperone-mediated stabilization function. Supporting Evidence: PMID:17563366 CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated.
GO:0031625 ubiquitin protein ligase binding	IPI PMID:8666824 Calreticulin binds hYRNA and the 52-kDa polypeptide componen...	KEEP AS NON CORE	Summary: Binding to the TRIM21/Ro52 (an E3 ligase) autoantigen; a specific but non-core interaction. Reason: Specific documented interaction (Ro/SS-A context); secondary to the ER chaperone role. Supporting Evidence: PMID:8666824 Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen.
GO:0044183 protein folding chaperone	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Protein folding chaperone is an accurate core molecular function for calreticulin. Reason: Calreticulin is a bona fide molecular chaperone. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0003729 mRNA binding	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: mRNA binding (p21 mRNA) reflects cytosolic moonlighting; non-core molecular function. Reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role. Supporting Evidence: PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate
GO:0017148 negative regulation of translation	TAS PMID:12242300 Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs a...	KEEP AS NON CORE	Summary: Cytosolic calreticulin represses translation of C/EBP mRNAs; a moonlighting activity, non-core. Reason: Documented cytosolic translational-repression moonlighting; secondary to the ER role. Supporting Evidence: PMID:12242300 Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins.
GO:0050821 protein stabilization	TAS PMID:10581245 Calreticulin functions in vitro as a molecular chaperone for...	ACCEPT	Summary: Protein stabilization via in vitro chaperone activity (glycosylated and non-glycosylated substrates); consistent with the core chaperone role. Reason: Supported chaperone-mediated stabilization function. Supporting Evidence: PMID:10581245 Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins.
GO:0001849 complement component C1q complex binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	KEEP AS NON CORE	Summary: C1q complex binding is a documented immune/extracellular function but non-core. Reason: Specific supported interaction relevant to complement/clearance; secondary to the ER role. Supporting Evidence: PMID:15474971 The protein also plays an important role in autoimmunity and cancer.
GO:0002502 peptide antigen assembly with MHC class I protein complex	ISS PMID:11825569 Assembly and antigen-presenting function of MHC class I mole...	KEEP AS NON CORE	Summary: MHC class I peptide antigen assembly is supported; CALR-null cells have impaired MHC I assembly. Reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. Supporting Evidence: PMID:11825569 Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin
GO:0008270 zinc ion binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	MARK AS OVER ANNOTATED	Summary: Zinc ion binding has been reported but is weakly supported relative to the well-characterized Ca2+-binding function; not a core function. Reason: Minor/uncertain metal-binding property; not a credible core molecular function.
GO:0009986 cell surface	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	KEEP AS NON CORE	Summary: Cell-surface localization is real (eat-me signal) but non-core. Reason: Documented surface exposure; secondary to ER function. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0030246 carbohydrate binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Carbohydrate (monoglucosylated N-glycan) binding is a core lectin molecular function. Reason: Underlies the lectin-chaperone activity of calreticulin. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0042824 MHC class I peptide loading complex	ISS PMID:11825569 Assembly and antigen-presenting function of MHC class I mole...	KEEP AS NON CORE	Summary: Calreticulin is a component of the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:11825569 Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin
GO:0050766 positive regulation of phagocytosis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Surface calreticulin promotes phagocytosis (eat-me signal); a real but non-core role. Reason: Documented immunogenic-cell-death/eat-me biology; secondary to ER function.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	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. Reason: Calreticulin is not a transcription factor; the effect is indirect via receptor sequestration and is non-core. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0005178 integrin binding	IPI PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: In vitro binding to the conserved KLGFFKR integrin alpha cytoplasmic-tail motif; a biochemically documented but cytosolic non-core interaction. Reason: Specific documented binding; cytosolic and not the conserved ER function. Supporting Evidence: PMID:1911778 a highly conserved motif in the cytoplasmic domain adjacent to the transmembrane domain of the alpha subunit of integrins
GO:0005634 nucleus	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Nuclear localization linked to the steroid-receptor moonlighting reports; a minor non-core pool. Reason: Minor nuclear pool tied to moonlighting; secondary to ER function.
GO:0005737 cytoplasm	IDA PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: Cytoplasmic localization supports cytosolic moonlighting functions; non-core. Reason: Documented cytoplasmic pool; secondary to ER function.
GO:0033144 negative regulation of intracellular steroid hormone receptor signaling pathway	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: In vitro inhibition of steroid receptor signaling via the KxFFKR motif; a documented but non-core moonlighting activity. Reason: Specific documented effect on steroid-receptor signaling; secondary to the ER chaperone function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0042921 nuclear receptor-mediated glucocorticoid signaling pathway	TAS PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Related to the glucocorticoid-receptor inhibition moonlighting role; non-core. Reason: Documented GR-related effect; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0045665 negative regulation of neuron differentiation	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	Summary: Derives from inhibition of retinoic-acid/nuclear-receptor signaling in the same in vitro study; over-broad downstream effect. Reason: Indirect downstream developmental effect of receptor inhibition; not a core function.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	Summary: Indirect transcriptional effect via nuclear-receptor sequestration; over-broad. Reason: Calreticulin is not a transcription factor; the effect is indirect and non-core. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0048387 negative regulation of retinoic acid receptor signaling pathway	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: In vitro inhibition of retinoic-acid receptor signaling via the KxFFKR motif; documented but non-core moonlighting. Reason: Specific documented effect on a nuclear receptor; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; descriptive non-core localization. Reason: Consistent with perinuclear ER; not a distinct functional compartment.
GO:0050681 nuclear androgen receptor binding	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Calreticulin binds the androgen receptor DNA-binding domain (KxFFKR motif) in vitro; a specific but non-core moonlighting interaction. Reason: Specific documented binding underlying the steroid-receptor inhibition; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0042981 regulation of apoptotic process	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	MARK AS OVER ANNOTATED	Summary: Apoptosis regulation is an over-broad downstream association from an apoptosis proteomics study. Reason: Over-broad BP; not a direct calreticulin molecular function.
GO:0005783 endoplasmic reticulum	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	ACCEPT	Summary: ER localization consistent with the core compartment. Reason: Matches the established ER localization.
GO:0003677 DNA binding	NAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	MARK AS OVER ANNOTATED	Summary: DNA binding is a non-authored-statement claim with weak support; not a credible core molecular function. Reason: Poorly supported; calreticulin is not a bona fide DNA-binding protein.
GO:0005509 calcium ion binding	TAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Calcium ion binding is a core conserved molecular function. Reason: Well-supported core Ca2+-binding function. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005788 endoplasmic reticulum lumen	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Direct ER lumen localization consistent with the core compartment. Reason: Reinforces the established ER-luminal localization.
GO:0005829 cytosol	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: A cytosolic pool supports the nuclear-export moonlighting role; non-core. Reason: Documented cytosolic pool; secondary to ER function.
GO:0006611 protein export from nucleus	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: Cytosolic calreticulin mediates nuclear export of the glucocorticoid receptor; a moonlighting activity, non-core. Reason: Documented nuclear-export moonlighting; secondary to the ER chaperone role. Supporting Evidence: PMID:11149926 Calreticulin Is a receptor for nuclear export.
GO:0006874 intracellular calcium ion homeostasis	TAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Regulation of intracellular calcium homeostasis is a core biological process for calreticulin. Reason: Calreticulin is the major ER Ca2+ store and regulates ER/intracellular Ca2+ handling. Supporting Evidence: PMID:15474971 The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity.
GO:0006355 regulation of DNA-templated transcription	TAS PMID:8107808 Modulation of gene expression by calreticulin binding to the...	MARK AS OVER ANNOTATED	Summary: Broad transcription-regulation claim from the glucocorticoid-receptor modulation study; indirect and over-broad. Reason: Calreticulin is not a transcription factor; the effect is indirect via receptor binding. Supporting Evidence: PMID:8107808 Modulation of gene expression by calreticulin binding to the glucocorticoid receptor.
GO:0005509 calcium ion binding	TAS PMID:7841019 Human placental calreticulin: purification, characterization...	ACCEPT	Summary: Calcium ion binding established in placental calreticulin characterization; core molecular function. Reason: Supports the well-established core Ca2+-binding function. Supporting Evidence: PMID:7841019 Human placental calreticulin: purification, characterization and association with other proteins.

Core Functions

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:

protein folding chaperone

Directly Involved In:

protein folding in endoplasmic reticulum

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

file:human/CALR/CALR-uniprot.txt
Calcium-binding chaperone that promotes folding, oligomeric
PMID:17563366
calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor

Lectin that recognizes monoglucosylated N-glycans, providing the carbohydrate-binding specificity that underlies glycoprotein quality control and retention of incompletely folded clients.

Molecular Function:

carbohydrate binding

Directly Involved In:

ERAD pathway

Cellular Locations:

endoplasmic reticulum quality control compartment

Supporting Evidence:

PMID:15056662
Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin

High-capacity calcium-binding protein that buffers ER calcium and regulates intracellular calcium homeostasis and ER calcium storage capacity.

Molecular Function:

calcium ion binding

Directly Involved In:

intracellular calcium ion homeostasis

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

PMID:15474971
The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10358038

Calreticulin is expressed on the cell surface of activated human peripheral blood T lymphocytes in association with major histocompatibility complex class I molecules.

Calreticulin is an ER-resident chaperone that is also displayed on the surface of activated T cells in association with MHC class I.

"the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells"

PMID:10581245

Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins.

Calreticulin acts as a molecular chaperone in vitro for both glycosylated and non-glycosylated substrates.

"Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins."

PMID:10605026

HLA-F is a predominantly empty, intracellular, TAP-associated MHC class Ib protein with a restricted expression pattern.

PMID:11149926

Calreticulin Is a receptor for nuclear export.

Cytosolic calreticulin can act as a nuclear export receptor for the glucocorticoid receptor.

"Calreticulin Is a receptor for nuclear export."

PMID:11825569

Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin.

Cells lacking calreticulin have impaired MHC class I assembly and antigen presentation.

"Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin"

PMID:11859136

Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading.

PMID:12242300

Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins.

PMID:14726956

Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate.

PMID:15056662

Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin independently of their assembly status.

Calreticulin binds MHC class I molecules in a monoglucosylated N-glycan-dependent manner.

"Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin"

PMID:15474971

Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum.

Calreticulin is a Ca2+-binding ER chaperone involved in calcium homeostasis, ER calcium storage, and secretory-pathway quality control.

"The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity."

PMID:15896298

In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.

PMID:15998798

Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade.

PMID:16130169

Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

PMID:16140380

Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR.

PMID:16502470

Human colostrum: identification of minor proteins in the aqueous phase by proteomics.

PMID:17055437

Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing.

PMID:17215244

Purification and identification of G protein-coupled receptor protein complexes under native conditions.

PMID:17563366

Calreticulin and Hsp90 stabilize the human insulin receptor and promote its mobility in the endoplasmic reticulum.

Calreticulin controls early maturation and stability of the human insulin receptor in the ER.

"both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER"

PMID:17916189

Identification of calreticulin as a ligand of GABARAP by phage display screening of a peptide library.

PMID:18177377

The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with MBL through the binding site for MBL-associated serine proteases.

PMID:19154346

Structural framework of the GABARAP-calreticulin interface--implications for substrate binding to endoplasmic reticulum chaperones.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20562859

Network organization of the human autophagy system.

PMID:21263072

Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules.

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

PMID:21590275

Calreticulin-2 is localized in the lumen of the endoplasmic reticulum but is not a Ca2+ -binding protein.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21705382

Characterization of unique signature sequences in the divergent maternal protein Bcl2l10.

PMID:21900206

A directed protein interaction network for investigating intracellular signal transduction.

PMID:22013210

The unfolded protein response: integrating stress signals through the stress sensor IRE1α.

PMID:22377355

Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.

PMID:22572157

Sensitive detection of idiotypic platelet-reactive alloantibodies by an electrical protein chip.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:23011799

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6.

PMID:23395171

Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation.

PMID:24325356

Somatic mutations of calreticulin in myeloproliferative neoplasms.

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.

PMID:24325359

Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.

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.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:25277244

The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.

PMID:26514267

Protein interactome mining defines melatonin MT1 receptors as integral component of presynaptic protein complexes of neurons.

PMID:27177927

Calreticulin-mutant proteins induce megakaryocytic signaling to transform hematopoietic cells and undergo accelerated degradation and Golgi-mediated secretion.

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.

PMID:28298427

Systematic protein-protein interaction mapping for clinically relevant human GPCRs.

PMID:30108113

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.

PMID:30188326

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:35405004

Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms.

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.

PMID:35948544

Molecular basis of MHC I quality control in the peptide loading complex.

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.

"peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan"

PMID:36417879

Calreticulin mutations affect its chaperone function and perturb the glycoproteome.

Disease-associated calreticulin mutations impair its chaperone function and broadly perturb the cellular glycoproteome.

"Calreticulin mutations affect its chaperone function and perturb the glycoproteome."

PMID:7841019

Human placental calreticulin: purification, characterization and association with other proteins.

PMID:8107808

Modulation of gene expression by calreticulin binding to the glucocorticoid receptor.

PMID:8107809

Inhibition of nuclear hormone receptor activity by calreticulin.

Calreticulin binds the DNA-binding domain of nuclear hormone receptors and inhibits their transcriptional activity in vitro.

"Inhibition of nuclear hormone receptor activity by calreticulin."

PMID:8418194

The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes.

Calreticulin is a major constituent of the lytic granules of cytolytic T lymphocytes.

"The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes."

PMID:8666824

Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen.

PMID:9640257

Calreticulin associates with non-HLA-A,-B class I proteins in the human choriocarcinoma cell lines JEG-3 and BeWo.

PMID:9922153

Evidence that C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin and interferes with complement activation.

C1q binds specifically to calreticulin, supporting calreticulin's role as a C1q-binding protein relevant to complement.

"C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin"

PMID:1911778

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.

Calreticulin binds the conserved KLGFFKR motif in the cytoplasmic tail of integrin alpha subunits in vitro.

"a highly conserved motif in the cytoplasmic domain adjacent to the transmembrane domain of the alpha subunit of integrins"

Reactome:R-HSA-1791082

Expression of Calreticulin

Reactome:R-HSA-2247514

SCARF1:ligand is endocytosed

Reactome:R-HSA-2507854

MSR1:ligand (SCARA1:ligand, SR-A:ligand) is endocytosed

Reactome:R-HSA-535717

Binding of calnexin/calreticulin to the unfolded protein

Reactome:R-HSA-548890

Removal of the third glucose by glucosidase II and release from the chaperone

Reactome:R-HSA-8863858

SEC22B, CALR, STX4, TAP and TAPBP bind

Reactome:R-HSA-8863914

Transport of SEC22B, TAP and PLC from ER to ERGIC

Reactome:R-HSA-8951499

Loading of antigenic peptides on to class I MHC

Reactome:R-HSA-8951595

CALR, TAP, TAPBP dissociate from SEC22B:STX4

Reactome:R-HSA-901047

Binding of ERp57

Reactome:R-HSA-983142

Formation of peptide loading complex (PLC)

Reactome:R-HSA-983161

Dissociation of the Antigenic peptide:MHC:B2M peptide loading complex

file:human/CALR/CALR-uniprot.txt

CALR UniProtKB record (P27797)

file:human/CALR/CALR-notes.md

Manual CALR curation notes

Suggested Experiments

Experiment: 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.

Hypothesis: Surface-exposed calreticulin functions as a pro-phagocytic eat-me signal independently of its ER chaperone activity.

Type: phagocytosis assay with surface-calreticulin manipulation

Experiment: 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.

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.

Type: ER calcium and UPR profiling in isogenic CALR-mutant cell lines

Deep Research

Falcon

(CALR-deep-research-falcon.md)

Research report: Human **CALR** (Calreticulin) — functional annotation (UniProt **P27797**) Falcon Edison Scientific Literature 28 citations 1 artifacts 2026-06-07T05:17:10.886103

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human CALR (Calreticulin) — functional annotation (UniProt P27797)

1. Gene/protein identity verification (critical disambiguation)

The research target is human calreticulin, encoded by CALR (Homo sapiens), matching UniProt accession P27797. Independent sources in this corpus explicitly map CALR to UniProt P27797 and describe hallmark features concordant with UniProt: an ER luminal soluble protein with an N-terminal signal peptide, a C-terminal KDEL ER-retrieval motif, and a tripartite N/P/C domain architecture underpinning lectin-like chaperone and Ca2+-binding activities. (michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34, ibarra2022type1but pages 1-3)

2. Key concepts and definitions (current understanding)

2.1 Core definition

Calreticulin (CALR) is an endoplasmic reticulum (ER) resident Ca2+-binding protein and lectin-like molecular chaperone that supports ER proteostasis and luminal Ca2+ homeostasis. (michalak2024calreticulinendoplasmicreticulum pages 1-2, ibarra2022type1but pages 1-3)

2.2 Domain organization and biochemical roles

Protein architecture (functional modularity). CALR is commonly described as comprising:
- N-domain (globular): carbohydrate/polypeptide-binding functions, including interactions relevant to glycoprotein quality control. (michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34)
- P-domain (proline-rich arm): contains binding sites for key ER co-chaperones/oxidoreductases such as PDIA3/ERp57 (and additional partners), supporting oxidative folding. (michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34)
- C-domain (acidic, disordered): provides high-capacity, low-affinity Ca2+ binding via acidic residues and terminates in KDEL. (faiz2023investigatingtherole pages 30-34, ibarra2022type1but pages 1-3)

ER localization and retrieval. CALR is synthesized with an N-terminal signal peptide and terminates in KDEL, an ER retrieval signal supporting ER residency (via retrieval from the Golgi). (michalak2024calreticulinendoplasmicreticulum pages 1-2, ibarra2022type1but pages 1-3)

2.3 Primary pathway context: the calnexin/calreticulin cycle (ER glycoprotein folding quality control)

CALR functions as a lectin chaperone in the calnexin/calreticulin cycle, binding monoglucosylated N-glycans on nascent/misfolded glycoproteins and coordinating with partners including ERp57/PDIA3 and UGGT1 to promote correct folding; persistent misfolds are routed to ER-associated degradation (ERAD). (faiz2023investigatingtherole pages 30-34, varricchio2017calreticulinchallengesposed pages 9-11)

2.4 Ca2+ buffering and “gatekeeping”

A major conceptual framework in recent reviews is that CALR is a dominant ER luminal Ca2+ buffer/store and a Ca2+ “gatekeeper/sensor” for ER luminal events. CALR’s Ca2+-binding capacity and chaperone functions are described as intertwined, linking luminal Ca2+ availability to folding and stress responses. (michalak2024calreticulinendoplasmicreticulum pages 1-2)

3. Subcellular localization and where CALR acts

3.1 Canonical localization: ER lumen

CALR’s principal site of action is the ER lumen, supported by the signal peptide and the KDEL retrieval sequence. (michalak2024calreticulinendoplasmicreticulum pages 1-2, ibarra2022type1but pages 1-3)

3.2 Non-canonical/extracellular localization: cell surface exposure and secretion

Despite being an ER protein, CALR can appear at the cell surface or be secreted/released, particularly in stress and disease contexts. Importantly, CALR lacks a transmembrane domain, so surface association is mediated by noncanonical trafficking and/or partner-mediated interactions. (migliaccio2018dissectingphysicalstructure pages 1-3, reid2024microglialactivationand pages 39-43)

4. Recent developments and latest research (prioritizing 2023–2024)

4.1 CALR as an immunogenic cell death (ICD) determinant (2024)

A central 2024 consensus in immunology/oncology reviews is that surface-exposed CALR (ecto-CALR) is a defining “danger” signal (DAMP) and pro-phagocytic ‘eat-me’ cue during immunogenic cell death, contributing to dendritic-cell (DC) engagement, cross-priming, and durable anti-tumor immunity. (beltranvisiedo2024cytofluorometricassessmentof pages 1-4, janssens2024decodingimmunogeniccell pages 18-18)

Mechanistically, ecto-CALR is repeatedly framed as acting via binding to LRP1/CD91 on phagocytes/APCs. Recent reviews explicitly cite primary work supporting that cell-surface CALR initiates clearance through trans-activation of LRP (CD91/LRP1) and that CALR exposure integrates with other ICD hallmarks (e.g., ATP secretion). (janssens2024decodingimmunogeniccell pages 18-18)

A 2024 mechanistic ICD review focused on radiotherapy reiterates that surface-exposed CALR binds LRP1/CD91 on immature antigen-presenting cells, functioning as a “potent pro-phagocytic signal.” (reid2024microglialactivationand pages 39-43)

4.2 CALR exon 9 frameshift mutations in myeloproliferative neoplasms (MPNs): mechanism and statistics (2023–2024)

Mutation class and prevalence statistics

Across mechanistic and review sources in this corpus:
- CALR mutations are emphasized as exon 9 insertion/deletion frameshifts (+1 bp) that alter the C-terminus, remove KDEL, and generate a shared, novel positively charged tail. (radjasandirane2023structuralanddynamic pages 1-2, kramer2024antibodytargetingof pages 1-2, ibarra2022type1but pages 1-3)
- In essential thrombocythemia (ET), CALR mutations are reported to account for ~25–30% of patients; in broader MPN contexts, CALR mutations are reported as ~20% of MPN patients in one review-style source. (radjasandirane2023structuralanddynamic pages 1-2)
- The two canonical recurrent variants—type 1 del52 and type 2 ins5—represent ~80–85% of CALR-mutant cases, with one 2024 antibody-therapy review summarizing type 1 as ~50% and type 2 as ~30% of CALR-mutant patients. (radjasandirane2023structuralanddynamic pages 1-2, kramer2024antibodytargetingof pages 1-2)
- Another mechanistic disease paper summarizes that CALR mutations occur in ~40% of ET and PMF patients, and that ~80% of CALR mutations are type 1 or type 2. (ibarra2022type1but pages 1-3)

These numbers are not fully identical across sources, likely reflecting different denominators (ET-only vs ET+PMF vs all MPN; cohort composition; diagnostic criteria), but they consistently place CALR as a major MPN driver mutation class. (radjasandirane2023structuralanddynamic pages 1-2, ibarra2022type1but pages 1-3)

Mechanism: neomorphic MPL binding and ligand-independent signaling

A convergent mechanistic model is that mutant CALR gains a neomorphic ability to bind and activate the thrombopoietin receptor MPL, driving ligand-independent receptor activation and downstream JAK2/STAT, ERK, and AKT signaling.

A 2024 review focusing on antibody targeting summarizes that mutant CALR binds MPL through a combination of N-domain N-glycan recognition and contributions from the mutant basic C-terminus (including interactions with acidic patches on MPL), stabilizing MPL and promoting activation and cell-surface shuttling. (kramer2024antibodytargetingof pages 1-2)
A 2023 review-style mechanistic summary reports that mutant CALR binds MPL via the CALR N-domain at a site distinct from thrombopoietin (TPO), and that the interaction depends on MPL N-glycosylation and CALR N-domain residues, driving TPO-independent MPL activation and downstream signaling. (faiz2023investigatingtherole pages 40-44)
A widely cited primary study further supports MPL dependence and documents downstream activation (STAT3/5, ERK1/2, AKT) and trafficking/secretory pathway involvement in mutant CALR biology. (han2016calreticulinmutantproteinsinduce pages 1-2)

ER Ca2+ biology as a mechanistic differentiator (type 1 vs type 2)

A mechanistic 2022 study links CALR’s canonical Ca2+ role to mutant-specific oncogenic signaling biology: type 1 CALR mutants (relative to type 2) lose more Ca2+-binding acidic residues, directly impairing Ca2+ binding and leading to ER Ca2+ depletion with activation of the IRE1α/XBP1 UPR pathway; genetic/pharmacologic IRE1α/XBP1 inhibition selectively kills type 1 mutant CALR-expressing cells and suppresses disease in vivo. (ibarra2022type1but pages 1-3)

5. Current applications and real-world implementations

5.1 Molecular diagnostics in MPN

Because exon 9 CALR frameshift mutations are prevalent and mechanistically causal in ET/PMF and related MPNs, CALR mutation testing (alongside JAK2 and MPL) is integrated into contemporary MPN diagnostic frameworks and risk stratification discussions. (radjasandirane2023structuralanddynamic pages 1-2, ibarra2022type1but pages 1-3)

5.2 CALR in cancer immunology as an operational biomarker of ICD

In translational oncology, ecto-CALR is treated as a practical biomarker for immunogenic stress/death, including in method-development work providing protocols to quantify surface CALR exposure on patient-derived cells. (beltranvisiedo2024cytofluorometricassessmentof pages 1-4)

6. Therapeutic development landscape (2023–2024)

6.1 Mutant-CALR neoepitope targeting (expert perspective)

A 2024 expert review positions the shared mutant CALR C-terminus (created by exon 9 frameshift) as a cell-surface neoantigen and an attractive immunotherapy target. The review summarizes multiple mutant CALR-targeting antibody efforts (e.g., B3, 4D7, and other monoclonals/peptide antibodies) and highlights ongoing progress toward clinical translation. (kramer2024antibodytargetingof pages 1-2)

6.2 Clinical trials (active real-world implementation)

Mutant CALR peptide vaccine (NCT05025488).
- ClinicalTrials.gov (posted 2023): “Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm”; Phase 1, interventional, single-group, open-label; Recruiting; target enrollment 10; primary objective safety/tolerability. Vaccination schedule includes repeated dosing of mutant CALR peptides (with KLH helper in the first vaccine) plus Poly-ICLC as adjuvant/immune stimulant; maximum participation up to ~80 weeks. URL: https://clinicaltrials.gov/study/NCT05025488 (NCT05025488 chunk 1)

JNJ-88549968 (T-cell redirecting bispecific antibody) for CALR-mutated MPN (NCT06150157).
- ClinicalTrials.gov (2023): “A Study of JNJ-88549968 for the Treatment of Calreticulin (CALR)-Mutated Myeloproliferative Neoplasms”; Phase 1; Recruiting; estimated enrollment 220; includes dose escalation and expansion. Investigates JNJ-88549968 monotherapy and (in a US cohort for myelofibrosis) potential combination with JAK inhibitors (ruxolitinib or momelotinib). Start date 2023-12-20. URL: https://clinicaltrials.gov/study/NCT06150157 (NCT06150157 chunk 1)

7. Expert synthesis and interpretation

7.1 Unifying functional theme

Across ER cell biology, immunology, and hematologic malignancy, CALR can be viewed as a proteostasis–Ca2+ integrator. In its canonical state, it buffers luminal Ca2+ and enforces folding quality control through the calnexin/calreticulin cycle (with PDIA3/ERp57). Under stress, it can become an extracellularly visible immune signal (ecto-CALR), while specific exon 9 frameshift mutations repurpose CALR into an oncogenic cofactor that aberrantly activates MPL signaling. (michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34, janssens2024decodingimmunogeniccell pages 18-18, kramer2024antibodytargetingof pages 1-2)

7.2 Translational implications

In solid tumors, ecto-CALR–LRP1/CD91 biology underpins ICD-driven vaccination effects and is therefore relevant to rational combinations (e.g., radiotherapy + immunotherapy) and to biomarker design. (reid2024microglialactivationand pages 39-43, janssens2024decodingimmunogeniccell pages 18-18)
In MPNs, the shared neo-C-terminus of mutant CALR creates opportunities for mutation-specific immunotherapy, now reflected in active clinical trials and in dedicated 2024 antibody-targeting analyses. (kramer2024antibodytargetingof pages 1-2, NCT05025488 chunk 1, NCT06150157 chunk 1)

Evidence summary table

Category	Item	Evidence-backed notes	Key citations
Protein feature	Identity and ER-targeting motifs	Human CALR (UniProt P27797) is a 417-aa soluble endoplasmic reticulum protein with an N-terminal signal peptide (~17 aa) that targets it to the secretory pathway and a C-terminal KDEL retrieval motif that supports ER residency via Golgi-to-ER retrieval. Loss of KDEL is therefore a major functional consequence of pathogenic exon 9 frameshift mutations.	(michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34, ibarra2022type1but pages 1-3)
Protein feature	Domain architecture	CALR contains an N-domain, a proline-rich P-domain, and an acidic C-domain. The N-domain mediates glycan/polypeptide interactions, the P-domain binds co-chaperones including PDIA3/ERp57, and the acidic C-domain provides major low-affinity, high-capacity Ca2+ binding/storage functions.	(michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34, radjasandirane2023structuralanddynamic pages 1-2)
Canonical function/pathway	Lectin chaperone in the calnexin/calreticulin cycle	CALR is a lectin-like chaperone that recognizes monoglucosylated N-glycans on newly synthesized glycoproteins. In the ER quality-control cycle, CALR works with calnexin, UGGT1, and ERp57/PDIA3 to promote oxidative folding, reglucosylation of incompletely folded substrates, and routing of terminally misfolded proteins toward ER-associated degradation.	(faiz2023investigatingtherole pages 30-34, varricchio2017calreticulinchallengesposed pages 9-11)
Canonical function/pathway	ER Ca2+ buffering and gatekeeping	CALR is a major ER luminal Ca2+ buffer/store, with reports that it binds a large fraction of ER Ca2+ and acts as a Ca2+ sensor/gatekeeper for luminal processes. This Ca2+-dependent role is tightly coupled to its chaperone functions and to ER homeostasis under stress.	(michalak2024calreticulinendoplasmicreticulum pages 1-2, radjasandirane2023structuralanddynamic pages 1-2, migliaccio2018dissectingphysicalstructure pages 1-3)
Canonical function/pathway	UPR and ER-stress linkage	CALR function is integrated with ER proteostasis and unfolded protein response signaling. In particular, type 1 mutant CALR, which loses more acidic Ca2+-binding residues than type 2 mutant, directly impairs Ca2+ binding, depletes ER Ca2+, and activates the IRE1α/XBP1 arm of the UPR; pharmacologic or genetic IRE1α/XBP1 inhibition selectively impairs type 1 mutant CALR-driven disease models.	(ibarra2022type1but pages 1-3)
Localization	Primary localization: ER lumen	The principal site of CALR action is the ER lumen, where it supports glycoprotein folding and Ca2+ homeostasis. Its KDEL motif explains retention/retrieval to the ER despite trafficking through the early secretory pathway.	(michalak2024calreticulinendoplasmicreticulum pages 1-2, faiz2023investigatingtherole pages 30-34)
Localization	Non-ER localization under stress	CALR is not confined to the ER: it can relocalize to the cell surface, extracellular space, and other compartments under stress or in specific contexts. Cell-surface association is notable because CALR lacks a transmembrane helix and instead depends on partner-mediated membrane association or noncanonical trafficking routes.	(migliaccio2018dissectingphysicalstructure pages 1-3, reid2024microglialactivationand pages 39-43)
Disease/immune relevance	Ecto-CALR in immunogenic cell death (ICD)	During immunogenic cell death, stressed tumor cells expose CALR on their surface before or during apoptosis, converting an ER chaperone into a damage-associated molecular pattern and potent pro-phagocytic “eat-me” signal. Recent reviews emphasize ecto-CALR as a core ICD hallmark used to judge whether radiotherapy, chemotherapy, or nanomedicine regimens are immunogenic.	(reid2024microglialactivationand pages 39-43, migliaccio2018dissectingphysicalstructure pages 1-3)
Disease/immune relevance	LRP1/CD91 receptor axis	Surface-exposed CALR promotes engulfment by professional antigen-presenting cells through interaction with LRP1/CD91, especially on dendritic cells and macrophages. This CALR–LRP1 axis is central to cross-priming and anti-tumor immunity in ICD frameworks.	(reid2024microglialactivationand pages 39-43)
Disease/clinical relevance	Exon 9 frameshift mutations in MPNs	Somatic CALR driver mutations in myeloproliferative neoplasms are exon 9 insertions/deletions that create a +1 frameshift, replacing the normal acidic C-terminus with a shared, novel basic tail and removing KDEL. Across recent reviews, CALR mutations are reported in ~25–30% of essential thrombocythemia, ~20% of MPN overall, or ~40% of ET/PMF in some disease-focused summaries; type 1 (52-bp deletion) and type 2 (5-bp insertion) account for ~80% of CALR-mutant cases, with type 1 ~50% and type 2 ~30%.	(radjasandirane2023structuralanddynamic pages 1-2, ibarra2022type1but pages 1-3, kramer2024antibodytargetingof pages 1-2)
Disease/clinical relevance	MPL binding and JAK–STAT activation	Mutant CALR acquires a neomorphic interaction with the thrombopoietin receptor MPL: the N-domain recognizes MPL N-glycans while the mutant basic C-terminus contributes pathogenic receptor engagement/stabilization. This drives ligand-independent MPL activation and downstream JAK2/STAT, ERK, and AKT signaling, explaining the megakaryocytic bias of CALR-mutant disease.	(kramer2024antibodytargetingof pages 1-2, han2016calreticulinmutantproteinsinduce pages 1-2, faiz2023investigatingtherole pages 40-44, ibarra2022type1but pages 1-3)
Disease/clinical relevance	Mutant trafficking, secretion, and surface display	Loss of KDEL facilitates secretion and abnormal trafficking of mutant CALR, although mutant proteins can still be detected in ER/Golgi compartments. Mutant CALR also appears on the cell surface and in circulation, where recent reviews note potential immunomodulatory or immunosuppressive effects, broadening its relevance beyond cell-intrinsic MPL signaling.	(kramer2024antibodytargetingof pages 1-2, han2016calreticulinmutantproteinsinduce pages 1-2, faiz2023investigatingtherole pages 40-44)
Current applications/therapeutics	Diagnostics and molecular profiling	CALR exon 9 testing is now part of standard molecular workup for BCR-ABL1-negative MPNs because CALR, JAK2, and MPL mutations are largely mutually exclusive and diagnostically informative. Mutation subtype also contributes to prognostic stratification and therapeutic monitoring in contemporary MPN care.	(radjasandirane2023structuralanddynamic pages 1-2, ibarra2022type1but pages 1-3)
Current applications/therapeutics	Mutant-CALR targeted therapy and trials	2024 reviews highlight active development of mutant-CALR-targeting antibodies directed to the neo-C-terminus, exploiting the shared neoepitope created by exon 9 frameshifts. Clinical translation is underway: a CALR-mutant peptide vaccine trial is recruiting (NCT05025488), and a phase 1 study of JNJ-88549968 for CALR-mutated MPN is recruiting (NCT06150157); these programs reflect the field’s move from mechanistic insight to mutation-specific immunotherapy.	(kramer2024antibodytargetingof pages 1-2)

Table: This table summarizes core structural features, biological functions, localization, and disease relevance of human calreticulin (CALR), with emphasis on immunogenic cell death and CALR-mutant myeloproliferative neoplasms. It is useful as a compact evidence map linking canonical ER biology to current translational applications.

URLs and publication dates (selected key sources used here)

Michalak M. Calreticulin: Endoplasmic reticulum Ca2+ gatekeeper. Journal of Cellular and Molecular Medicine. 2024-07. https://doi.org/10.1111/jcmm.17839 (michalak2024calreticulinendoplasmicreticulum pages 1-2)
Radjasandirane R, de Brevern AG. Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia. Biomolecules. 2023-03. https://doi.org/10.3390/biom13030509 (radjasandirane2023structuralanddynamic pages 1-2)
Kramer F, Mullally A. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. Journal of Cellular and Molecular Medicine. 2024-08. https://doi.org/10.1111/jcmm.17896 (kramer2024antibodytargetingof pages 1-2)
Janssens S, Rennen S, Agostinis P. Decoding immunogenic cell death from a dendritic cell perspective. Immunological Reviews. 2024-12. https://doi.org/10.1111/imr.13301 (janssens2024decodingimmunogeniccell pages 18-18)
Beltrán-Visiedo M, et al. Cytofluorometric assessment of calreticulin exposure on CD38+ plasma cells from the human bone marrow. Methods in Cell Biology. 2024-01. https://doi.org/10.1016/bs.mcb.2024.05.009 (beltranvisiedo2024cytofluorometricassessmentof pages 1-4)
Galassi C, et al. Molecular determinants of immunogenic cell death elicited by radiation therapy. Immunological Reviews. 2024-09. https://doi.org/10.1111/imr.13271 (reid2024microglialactivationand pages 39-43)
ClinicalTrials.gov. NCT05025488: Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm. 2023. https://clinicaltrials.gov/study/NCT05025488 (NCT05025488 chunk 1)
ClinicalTrials.gov. NCT06150157: A Study of JNJ-88549968 for the Treatment of CALR-Mutated MPNs. 2023. https://clinicaltrials.gov/study/NCT06150157 (NCT06150157 chunk 1)

References

(michalak2024calreticulinendoplasmicreticulum pages 1-2): Marek Michalak. Calreticulin: endoplasmic reticulum ca2+ gatekeeper. Journal of Cellular and Molecular Medicine, Jul 2024. URL: https://doi.org/10.1111/jcmm.17839, doi:10.1111/jcmm.17839. This article has 59 citations and is from a peer-reviewed journal.
(faiz2023investigatingtherole pages 30-34): NMA Faiz. Investigating the role of endoplasmic reticulum (er) homeostasis in normal and calreticulin (calr) mutant megakaryocyte maturation. Unknown journal, 2023.
(ibarra2022type1but pages 1-3): Juan Ibarra, Yassmin A. Elbanna, Katarzyna Kurylowicz, Michele Ciboddo, Harrison S. Greenbaum, Nicole S. Arellano, Deborah Rodriguez, Maria Evers, Althea Bock-Hughes, Chenyu Liu, Quinn Smith, Julian Lutze, Julian Baumeister, Milena Kalmer, Kathrin Olschok, Benjamin Nicholson, Diane Silva, Luke Maxwell, Jonathan Dowgielewicz, Elisa Rumi, Daniela Pietra, Ilaria Carola Casetti, Silvia Catricala, Steffen Koschmieder, Sandeep Gurbuxani, Rebekka K. Schneider, Scott A. Oakes, and Shannon E. Elf. Type 1 but not type 2 calreticulin mutations activate the ire1a/xbp1 pathway of the unfolded protein response to drive myeloproliferative neoplasms. Blood cancer discovery, 3:298-315, Apr 2022. URL: https://doi.org/10.1158/2643-3230.bcd-21-0144, doi:10.1158/2643-3230.bcd-21-0144. This article has 38 citations and is from a peer-reviewed journal.
(varricchio2017calreticulinchallengesposed pages 9-11): Lilian Varricchio, Mario Falchi, Massimiliano Dall'Ora, Caterina De Benedittis, Alessandra Ruggeri, Vladimir N. Uversky, and Anna Rita Migliaccio. Calreticulin: challenges posed by the intrinsically disordered nature of calreticulin to the study of its function. Frontiers in Cell and Developmental Biology, Nov 2017. URL: https://doi.org/10.3389/fcell.2017.00096, doi:10.3389/fcell.2017.00096. This article has 45 citations.
(migliaccio2018dissectingphysicalstructure pages 1-3): Anna Rita Migliaccio and Vladimir N. Uversky. Dissecting physical structure of calreticulin, an intrinsically disordered ca2+-buffering chaperone from endoplasmic reticulum. Journal of Biomolecular Structure and Dynamics, 36:1617-1636, Apr 2018. URL: https://doi.org/10.1080/07391102.2017.1330224, doi:10.1080/07391102.2017.1330224. This article has 26 citations and is from a peer-reviewed journal.
(reid2024microglialactivationand pages 39-43): Microglial activation and regulation by secreted chaperones This article has 0 citations.
(beltranvisiedo2024cytofluorometricassessmentof pages 1-4): Manuel Beltrán-Visiedo, Alfonso Serrano-Del Valle, Nelia Jiménez-Aldúan, Ruth Soler-Agesta, Javier Naval, Lorenzo Galluzzi, and Isabel Marzo. Cytofluorometric assessment of calreticulin exposure on cd38+ plasma cells from the human bone marrow. Methods in cell biology, 189:189-206, Jan 2024. URL: https://doi.org/10.1016/bs.mcb.2024.05.009, doi:10.1016/bs.mcb.2024.05.009. This article has 2 citations and is from a peer-reviewed journal.
(janssens2024decodingimmunogeniccell pages 18-18): Sophie Janssens, Sofie Rennen, and Patrizia Agostinis. Decoding immunogenic cell death from a dendritic cell perspective. Immunological Reviews, 321:350-370, Dec 2024. URL: https://doi.org/10.1111/imr.13301, doi:10.1111/imr.13301. This article has 79 citations and is from a domain leading peer-reviewed journal.
(radjasandirane2023structuralanddynamic pages 1-2): Ragousandirane Radjasandirane and Alexandre G. de Brevern. Structural and dynamic differences between calreticulin mutants associated with essential thrombocythemia. Biomolecules, 13:509, Mar 2023. URL: https://doi.org/10.3390/biom13030509, doi:10.3390/biom13030509. This article has 10 citations.
(kramer2024antibodytargetingof pages 1-2): Frederike Kramer and Ann Mullally. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. Journal of Cellular and Molecular Medicine, Aug 2024. URL: https://doi.org/10.1111/jcmm.17896, doi:10.1111/jcmm.17896. This article has 8 citations and is from a peer-reviewed journal.
(faiz2023investigatingtherole pages 40-44): NMA Faiz. Investigating the role of endoplasmic reticulum (er) homeostasis in normal and calreticulin (calr) mutant megakaryocyte maturation. Unknown journal, 2023.
(han2016calreticulinmutantproteinsinduce pages 1-2): Lijuan Han, Claudia Schubert, Johanna Köhler, Mirle Schemionek, Susanne Isfort, Tim H. Brümmendorf, Steffen Koschmieder, and Nicolas Chatain. Calreticulin-mutant proteins induce megakaryocytic signaling to transform hematopoietic cells and undergo accelerated degradation and golgi-mediated secretion. Journal of Hematology & Oncology, May 2016. URL: https://doi.org/10.1186/s13045-016-0275-0, doi:10.1186/s13045-016-0275-0. This article has 121 citations and is from a domain leading peer-reviewed journal.
(NCT05025488 chunk 1): Marina Kremyanskaya. Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm. Marina Kremyanskaya. 2023. ClinicalTrials.gov Identifier: NCT05025488
(NCT06150157 chunk 1): A Study of JNJ-88549968 for the Treatment of Calreticulin (CALR)-Mutated Myeloproliferative Neoplasms. Janssen Research & Development, LLC. 2023. ClinicalTrials.gov Identifier: NCT06150157

Artifacts

Edison artifact artifact-00

Citations

michalak2024calreticulinendoplasmicreticulum pages 1-2
janssens2024decodingimmunogeniccell pages 18-18
reid2024microglialactivationand pages 39-43
radjasandirane2023structuralanddynamic pages 1-2
kramer2024antibodytargetingof pages 1-2
faiz2023investigatingtherole pages 40-44
han2016calreticulinmutantproteinsinduce pages 1-2
beltranvisiedo2024cytofluorometricassessmentof pages 1-4
faiz2023investigatingtherole pages 30-34
varricchio2017calreticulinchallengesposed pages 9-11
migliaccio2018dissectingphysicalstructure pages 1-3
https://clinicaltrials.gov/study/NCT05025488
https://clinicaltrials.gov/study/NCT06150157
https://doi.org/10.1111/jcmm.17839
https://doi.org/10.3390/biom13030509
https://doi.org/10.1111/jcmm.17896
https://doi.org/10.1111/imr.13301
https://doi.org/10.1016/bs.mcb.2024.05.009
https://doi.org/10.1111/imr.13271
https://doi.org/10.1111/jcmm.17839,
https://doi.org/10.1158/2643-3230.bcd-21-0144,
https://doi.org/10.3389/fcell.2017.00096,
https://doi.org/10.1080/07391102.2017.1330224,
https://doi.org/10.1016/bs.mcb.2024.05.009,
https://doi.org/10.1111/imr.13301,
https://doi.org/10.3390/biom13030509,
https://doi.org/10.1111/jcmm.17896,
https://doi.org/10.1186/s13045-016-0275-0,

📚 Additional Documentation

Notes

(CALR-notes.md)

CALR (Calreticulin, P27797) curation notes

Overview

CALR is the soluble ER-luminal paralog of calnexin, one of the two central ER lectin
chaperones of the calnexin/calreticulin (CNX/CRT) cycle. It binds monoglucosylated
N-glycans (Glc1Man9GlcNAc2) on nascent glycoproteins, recruits ERp57 (PDIA3) for
oxidative folding, retains/triages misfolded glycoproteins for ER quality control,
and is a major high-capacity Ca2+-binding protein that regulates ER calcium storage.
It is a key chaperone in MHC class I peptide loading. Beyond the ER, CALR has
well-documented secondary roles: a cell-surface/extracellular "eat-me" signal driving
immunogenic cell death and phagocytosis, and a variety of context-specific reported
functions (integrin cytoplasmic-tail binding, nuclear-export receptor for steroid
receptors, transcriptional/translational modulation).

Core function evidence

UniProt FUNCTION [file:human/CALR/CALR-uniprot.txt]:
"Calcium-binding chaperone that promotes folding, oligomeric assembly and quality
control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle. This
lectin interacts transiently with almost all of the monoglucosylated glycoproteins
that are synthesized in the ER".
Review [PMID:15474971 "Calreticulin is a 46-kDa Ca2+-binding chaperone found across a
diverse range of species. The protein is involved in the regulation of intracellular
Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity. Calreticulin is
also an important molecular chaperone involved in "quality control" within secretory
pathways."]. This review supports the calcium-binding, chaperone, and quality-control
core functions (TAS-grade synthesis source).
Lectin/glycan binding: CALR binds monoglucosylated MHC I glycans; PMID:15056662 Carbohydrate
binding (GO:0030246) is a core MF.
MHC class I peptide loading complex (PLC): CALR is a structural component of the PLC
and supports peptide-receptive MHC I. PMID:35948544 CALR-null cells have impaired MHC I
assembly [PMID:11825569 title]. This is a specialized but well-supported application of
the core chaperone function; I treat PLC membership / peptide antigen assembly as
core-adjacent (ACCEPT for the direct IDA in the human PLC structure paper, KEEP_AS_NON_CORE
for ISS transfers).
Client chaperone examples: insulin receptor PMID:17563366. Mutant CALR perturbs the glycoproteome PMID:36417879.

Calcium

Ca2+ binding (IBA, IEA, TAS PMID:15474971, TAS PMID:7841019, TAS PMID:11149926):
core. CALR is the major high-capacity low-affinity Ca2+ store of the ER. The IMP from
PMID:21705382 is about Bcl2l10 signature sequences, weak for CALR directly.
intracellular calcium ion homeostasis (TAS PMID:11149926): core ER calcium role.

Cell surface / extracellular ("eat-me" / immunogenic cell death) — REAL but non-core

Cell surface localization on activated T cells, in association with MHC I
PMID:10358038. Surface CALR is the prototypic
pre-apoptotic "eat-me" signal driving phagocytosis (GO:0050766 positive regulation of
phagocytosis); a real biology but secondary to the ER chaperone role -> KEEP_AS_NON_CORE.
C1q binding (GO:0001849): CALR (cC1qR) binds the C1q collagen-like tail; relevant to
apoptotic-cell clearance and complement [PMID:9922153 title]. Non-core.
Cytolytic/lytic granule (GO:0044194 EXP PMID:8418194): CALR is a major constituent of
CTL lytic granules; real localization, non-core.
Extracellular region/matrix/exosome (HDA, IEA, TAS): secreted/extracellular pools exist
but are non-core.
Endothelial/trophoblast migration (PMID:22377355), dendritic cell chemotaxis (PMID:16140380
via C1q/gC1qR), substrate adhesion/spreading (PMID:11859136): context-specific extracellular/
surface activities -> KEEP_AS_NON_CORE.

Nuclear / cytosolic moonlighting — non-core / over-annotated

Nuclear export receptor activity (GO:0005049) and protein export from nucleus (GO:0006611):
cytosolic CALR was reported to export the glucocorticoid receptor DNA-binding domain
PMID:11149926. Real but minor/disputed
moonlighting; KEEP_AS_NON_CORE.
Nuclear hormone receptor inhibition / negative regulation of transcription / steroid receptor
signaling (PMID:8107809, PMID:8107808): CALR binds the KxFFKR motif in the GR/AR/RAR
DNA-binding domain and inhibits their activity in vitro PMID:8107809. The cluster of transcription/steroid-signaling
BP terms (GO:0000122, GO:0045892, GO:0033144, GO:0042921, GO:0048387, GO:0045665, GO:0006355,
GO:0050681, GO:0010628 etc.) derive from this in-vitro work and ortholog transfer; the
DNA-binding domain motif interaction is the same one used for integrin binding (KLGFFKR).
Mark the bare transcription/steroid BP terms as over-annotated or non-core; keep the specific
androgen-receptor binding as non-core.
Integrin binding (GO:0005178, PMID:1911778): in-vitro binding to KLGFFKR integrin alpha
cytoplasmic tail peptide; biochemically real but cytosolic and not the conserved ER function
-> KEEP_AS_NON_CORE.
mRNA binding / negative regulation of translation (PMID:14726956 p21, PMID:12242300 C/EBP):
cytosolic CALR reported to bind specific mRNAs and repress translation; moonlighting,
non-core. The associated cell-cycle/senescence/proliferation BP terms (PMID:14726956) are
downstream and over-broad.
RNA binding (GO:0003723 HDA PMID:22658674), DNA binding (GO:0003677 NAS), zinc/iron ion
binding (GO:0008270, GO:0005506): high-throughput or weakly supported; over-annotated for a
functional MF.

Over-broad ortholog (GO_REF:0000107) phenotype/response cluster

A large block of IEA Ensembl-Compara terms: spermatogenesis, cardiac muscle cell
differentiation, cellular response to electrical stimulus/lithium/virus, response to
estradiol/testosterone/peptide/glycoside/biphenyl/xenobiotic, senescence, cell-cycle,
postsynapse/glutamatergic synapse, acrosomal vesicle, etc. These are phenotype-/response-
transfer over-annotations; most -> MARK_AS_OVER_ANNOTATED, a few developmental ones (cardiac)
reflect the mouse CALR-knockout cardiac phenotype and are KEEP_AS_NON_CORE at most.

protein binding (GO:0005515) cluster

Numerous IPI "protein binding" annotations from interactome maps and individual partner
studies (HLA-F/HLA-E, GABARAP, MBL, ERp57, etc.). Per guidelines, bare "protein binding"
is uninformative -> MARK_AS_OVER_ANNOTATED.

Summary of core functions

MF: monoglucosylated N-glycan (carbohydrate) binding lectin / unfolded protein binding
chaperone activity in the ER lumen.
MF: calcium ion binding (high-capacity ER Ca2+ buffering).
BP: protein folding / glycoprotein quality control in the ER (CNX/CRT cycle); protein
maturation/stabilization.
BP: peptide antigen assembly with MHC class I (PLC) — specialized but well supported.
BP: ERAD pathway (triage of terminally misfolded clients).
CC: endoplasmic reticulum lumen.
Secondary (non-core): cell-surface eat-me signal / phagocytosis, extracellular pools,
C1q binding, cytosolic/nuclear moonlighting (nuclear export, integrin binding, mRNA binding).

Falcon deep research findings (2026-06-07)

The Falcon report (CALR-deep-research-falcon.md) overwhelmingly CONFIRMS the existing
review for canonical biology (ER-luminal lectin chaperone of the CNX/CRT cycle, binds
monoglucosylated N-glycans, recruits ERp57/PDIA3 via the P-domain, high-capacity/low-affinity
ER Ca2+ buffer, KDEL retrieval, ecto-CALR eat-me/ICD role). The genuinely NEW material is the
oncogenic exon 9 mutant-CALR / MPN axis, which is entirely absent from the existing
existing_annotations (correctly, since these are neomorphic disease mutations not in GOA),
plus a more explicit receptor mechanism for the eat-me signal. Key points:

NEW (disease, well established): Somatic exon 9 frameshift (+1 bp) CALR mutations are driver
lesions in JAK2/MPL-nonmutated myeloproliferative neoplasms (essential thrombocythemia,
primary myelofibrosis), replacing the acidic Ca2+-binding C-terminus + KDEL with a shared
novel basic tail. First described in two 2013 NEJM papers [PMID:24325356 "Somatic insertions
or deletions in exon 9 of CALR"; PMID:24325359 "Mutations were located in exon 9 and
generated a +1 base-pair frameshift"]. Type 1 (del52) and type 2 (ins5) ~80% of mutant cases.
This is mutation biology, not a function of WT CALR -> does NOT alter existing_annotations;
recorded here and as statement-only references for context.
NEW (mechanism): Mutant CALR gains a neomorphic, ligand(TPO)-independent interaction with the
thrombopoietin receptor MPL (N-domain recognition of MPL N-glycans plus the mutant basic
C-terminus), driving constitutive JAK2/STAT5(3), ERK1/2 and AKT activation and megakaryocytic
transformation; MPL is required [PMID:27177927 Han 2016 "Exogenous expression of MPL led to
constitutive activation of STAT3 and 5, ERK1/2, and AKT, cytokine-independent growth"]. Mutant
CALR also shows accelerated degradation and Golgi-mediated secretion (same paper).
NEW (mechanism, ties to Ca2+ core): Type 1 (but not type 2) mutants lose more acidic
Ca2+-binding residues, directly impairing Ca2+ binding -> ER Ca2+ depletion -> selective
activation of the IRE1alpha/XBP1 UPR arm; IRE1alpha/XBP1 inhibition selectively kills type 1
mutant cells in vivo [PMID:35405004 Ibarra 2022 "loss of Ca2+ binding residues in the type I
mutant CALR protein directly impairs its Ca2+ binding ability...activation of the IRE1alpha/XBP1
pathway"]. Mechanistically links the WT high-capacity Ca2+-buffer function to disease.
CONFIRMS + refines (interaction/pathway): ecto-CALR drives pro-phagocytic clearance via the
LRP1/CD91 receptor on phagocytes/APCs (the existing review notes phagocytosis/eat-me and SCARF1/
MSR1 scavenger receptors but not LRP1/CD91 by name). Falcon supports this only via 2024 review
sources (janssens2024, reid/galassi2024), not primary data -> treat as PROVISIONAL receptor
detail; not used to change annotations. GO:0050766 (positive regulation of phagocytosis) already
KEEP_AS_NON_CORE.
CONFIRMS (translational, not GO-actionable): mutant-CALR neo-C-terminus is a cell-surface
neoantigen; active immunotherapy programs (peptide vaccine NCT05025488; bispecific JNJ-88549968
NCT06150157) and antibody efforts (kramer2024 review). Context only; no annotation impact.
Provenance caveats: Falcon's quantitative MPN prevalence figures vary across sources
(~20% MPN / ~25-30% ET / ~40% ET+PMF) due to different denominators; the Faiz 2023 source is a
thesis ("Unknown journal") and reid2024 has 0 citations -> low-confidence, kept out of the YAML.
Only the four primary/peer-reviewed PMIDs above were resolved (via PubMed) and added as
statement-only references.

Pn Notes

(CALR-pn-notes.md)

CALR PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P27797
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CALR/CALR-ai-review.yaml
AIGR review HTML: present - genes/human/CALR/CALR-ai-review.html
Gene notes: present - genes/human/CALR/CALR-notes.md
GOA TSV: present - genes/human/CALR/CALR-goa.tsv
UniProt record: present - genes/human/CALR/CALR-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CALR.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CALR.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/CALR/CALR-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 43; KEEP_AS_NON_CORE: 69; MARK_AS_OVER_ANNOTATED: 53

PN Consistency Summary

Consistency: Biology consistent across review, notes, deep-research, and PN — calreticulin is the soluble ER-luminal lectin chaperone of the CNX/CRT cycle binding monoglucosylated N-glycans, also the major ER Ca2+ buffer and an MHC-I PLC component. As with CANX, the PROJECTED GO term conflicts with this role.
PN story / NEW pressure: GO:0006487 (VERIFIED real) = the process of ADDING the N-glycan; calreticulin binds the pre-formed glycan, it is not a glycosyltransferase. The review correctly represents function as GO:0030246 carbohydrate binding (ACCEPT), GO:0044183 protein folding chaperone, GO:0006457 protein folding, GO:0036503 ERAD, plus Ca2+ binding and MHC-I PLC roles. GO:0006487 absent from CALR GOA (confirmed). Conclude: OVER-REACHES — same category error as CANX; do NOT add.
Evidence alignment: PN node carries no reference titles; review well-evidenced (PMID:15474971 review, PMID:35948544 PLC structure, PMID:17563366 insulin-receptor chaperoning, PMID:10358038 surface CALR). Review also flags two wrong-gene reference mis-assignments at source (PMID:21705382→Bcl2l10; PMID:21590275→CALR3) — unrelated to the PN mapping but worth noting for REF hygiene. No shared evidence supports an N-glycosylation-process claim.
Verdict: OVER-REACHES — reject projected GO:0006487 for CALR (true lectin-chaperone function already captured). Recommended edits: [MAP] do not propagate GO:0006487 to CALR; re-map the shared "Lectin chaperone" type node to a binding/chaperone term (GO:0030246 / GO:0036503), covering CALR+CANX together.

Full Consistency Review

UniProt: P27797 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (exhaustive; ~80 annotations, notes + falcon deep-research present)
PN placement: ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone ; PN-node mapping: type (Lectin chaperone)→no_mapping; group (N-glycosylation system)→GO:0006487 protein N-linked glycosylation (mapped/ok_for_propagation); class/branch→no_mapping. (Identical node + mapping to CANX, its membrane-bound paralog.)
Consistency: Biology consistent across review, notes, deep-research, and PN — calreticulin is the soluble ER-luminal lectin chaperone of the CNX/CRT cycle binding monoglucosylated N-glycans, also the major ER Ca2+ buffer and an MHC-I PLC component. As with CANX, the PROJECTED GO term conflicts with this role.
PN story / NEW pressure: GO:0006487 (VERIFIED real) = the process of ADDING the N-glycan; calreticulin binds the pre-formed glycan, it is not a glycosyltransferase. The review correctly represents function as GO:0030246 carbohydrate binding (ACCEPT), GO:0044183 protein folding chaperone, GO:0006457 protein folding, GO:0036503 ERAD, plus Ca2+ binding and MHC-I PLC roles. GO:0006487 absent from CALR GOA (confirmed). Conclude: OVER-REACHES — same category error as CANX; do NOT add.
Mapping strategy: Same fix as CANX — the lectin-chaperone members of the "N-glycosylation system" group should not inherit the enzymatic GO:0006487; the "Lectin chaperone" type node should carry a binding/chaperone mapping instead. This is one shared correction covering both CALR and CANX.
Evidence alignment: PN node carries no reference titles; review well-evidenced (PMID:15474971 review, PMID:35948544 PLC structure, PMID:17563366 insulin-receptor chaperoning, PMID:10358038 surface CALR). Review also flags two wrong-gene reference mis-assignments at source (PMID:21705382→Bcl2l10; PMID:21590275→CALR3) — unrelated to the PN mapping but worth noting for REF hygiene. No shared evidence supports an N-glycosylation-process claim.
Verdict: OVER-REACHES — reject projected GO:0006487 for CALR (true lectin-chaperone function already captured). Recommended edits: [MAP] do not propagate GO:0006487 to CALR; re-map the shared "Lectin chaperone" type node to a binding/chaperone term (GO:0030246 / GO:0036503), covering CALR+CANX together.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CALR/CALR-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

UniProt: P27797
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [group] ER proteostasis|Glycoproteostasis|N-glycosylation system
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006487 protein N-linked glycosylation]
  rationale: This PN group captures the ER N-glycosylation machinery that installs and processes N-linked glycans during proteostasis. GO protein N-linked glycosylation is the best current propagation target in the local cache.
- [class] ER proteostasis|Glycoproteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0006487 protein N-linked glycosylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

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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: []

CALR

Gene Description

Existing Annotations Review

Core Functions

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.

Lectin that recognizes monoglucosylated N-glycans, providing the carbohydrate-binding specificity that underlies glycoprotein quality control and retention of incompletely folded clients.

High-capacity calcium-binding protein that buffers ER calcium and regulates intracellular calcium homeostasis and ER calcium storage capacity.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human CALR (Calreticulin) — functional annotation (UniProt P27797)

1. Gene/protein identity verification (critical disambiguation)

2. Key concepts and definitions (current understanding)

2.1 Core definition

2.2 Domain organization and biochemical roles

2.3 Primary pathway context: the calnexin/calreticulin cycle (ER glycoprotein folding quality control)

2.4 Ca2+ buffering and “gatekeeping”

3. Subcellular localization and where CALR acts

3.1 Canonical localization: ER lumen

3.2 Non-canonical/extracellular localization: cell surface exposure and secretion

4. Recent developments and latest research (prioritizing 2023–2024)

4.1 CALR as an immunogenic cell death (ICD) determinant (2024)

4.2 CALR exon 9 frameshift mutations in myeloproliferative neoplasms (MPNs): mechanism and statistics (2023–2024)

Mutation class and prevalence statistics

Mechanism: neomorphic MPL binding and ligand-independent signaling

ER Ca2+ biology as a mechanistic differentiator (type 1 vs type 2)

5. Current applications and real-world implementations

5.1 Molecular diagnostics in MPN

5.2 CALR in cancer immunology as an operational biomarker of ICD

6. Therapeutic development landscape (2023–2024)

6.1 Mutant-CALR neoepitope targeting (expert perspective)

6.2 Clinical trials (active real-world implementation)

7. Expert synthesis and interpretation

7.1 Unifying functional theme

7.2 Translational implications

Evidence summary table

URLs and publication dates (selected key sources used here)

Artifacts

Citations

📚 Additional Documentation

Notes

CALR (Calreticulin, P27797) curation notes

Overview

Core function evidence

Calcium

Cell surface / extracellular ("eat-me" / immunogenic cell death) — REAL but non-core

Nuclear / cytosolic moonlighting — non-core / over-annotated

Over-broad ortholog (GO_REF:0000107) phenotype/response cluster

protein binding (GO:0005515) cluster

Summary of core functions

Falcon deep research findings (2026-06-07)

Pn Notes

CALR PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

Projected GO annotations (1)

Note

📄 View Raw YAML