Alternative titles; symbols
HGNC Approved Gene Symbol: CALR
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:12,938,609-12,944,489 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Myelofibrosis, somatic | 254450 | 3 | |
| Thrombocythemia, somatic | 187950 | 3 |
Calreticulin is a multifunctional protein that acts as a major Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum. It is also found in the nucleus, suggesting that it may have a role in transcription regulation (Burns et al., 1994).
Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. McCauliffe et al. (1990) showed that calreticulin binds to antibodies in certain sera of systemic lupus and Sjogren patients which contain anti-Ro/SSA antibodies, that it is highly conserved among species, and that it is located in the endoplasmic and sarcoplasmic reticulum where it may bind calcium. With synthetic oligonucleotides corresponding to the amino acid sequence, McCauliffe et al. (1990) isolated full-length CALR cDNA that encodes a human Ro ribonucleoprotein autoantigen. The deduced 417-amino acid protein has a predicted molecular mass of 48 kD. Southern filter hybridization analysis showed that the CALR gene is not highly polymorphic and exists in single copy in the human genome.
Frank (1994) pointed out that the CALR gene mapped to chromosome 19p encodes the 48-kD calreticulin, a protein with Ro/SSA properties. Itoh et al. (1991) showed that the 52-kD and the 60-kD forms of Ro/SSA ribonucleoproteins are encoded by separate genes mapping to chromosome 11 (TRIM21; 109092) and chromosome 1 (TROVE2; 600063), respectively.
By Northern blot analysis of human tissues, Persson et al. (2002) found ubiquitous expression of a 1.9-kb CALR transcript.
Burns et al. (1994) reported that the amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Dedhar et al. (1994) showed that calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
Boehm et al. (1994) showed that SLE is associated with increased autoantibody titers against calreticulin but that calreticulin is not a Ro/SS-A antigen. Orth et al. (1996) found increased autoantibody titers against human calreticulin in infants with complete congenital heart block (234700) of both the IgG and IgM classes.
THBS1 (188060) or a peptide of the 19-amino acid active site in its heparin-binding domain signals focal adhesion disassembly through interaction with a cell surface form of CRT. Using bovine aortic endothelial cells and wildtype and low density lipoprotein receptor-related protein (LRP, or LRP1; 107770) -/- mouse fibroblasts, Orr et al. (2003) showed that Lrp interacted with Crt and was required to mediate focal adhesion disassembly and downstream signaling for reorganization of focal adhesions. Binding of the LRP ligand RAP (LRPAP1; 104225) to purified human LRP inhibited interaction between recombinant human CRT and LRP.
Gardai et al. (2005) stated that calreticulin on the surface of apoptotic cells serves as a recognition and clearance ligand by activating the internalization receptor LRP1 (107770) on the responding phagocyte cell surface. Using mouse and human cells, they found that the surface expression of calreticulin increased and calreticulin was redistributed during apoptosis, possibly enhancing stimulation of LRP1 on the phagocyte. In addition, CD47 (601028) on the apoptotic cell surface was altered and/or lost, which reduced the activation of SIRP-alpha (PTPNS1; 602461) on the phagocytic cell surface, resulting in phagocytosis.
In CT26 mouse colon cancer cells, Obeid et al. (2007) demonstrated that anthracyclins induced immunogenic cell death by way of a rapid, preapoptotic translocation of calreticulin to the cell surface. Blockade or knockdown of Calr suppressed phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. Anthracyclin-induced Calr translocation was mimicked by inhibition of the protein phosphatase-1 (see PPP1CA; 176875)/Gadd34 (PPP1R15A; 611048) complex. Administration of recombinant Calr or inhibitors of Pp1/Gadd34 restored immunogenicity of cell death elicited by etoposide and mitomycin C and enhanced their antitumor effects in vivo. Obeid et al. (2007) concluded that CALR plays a key role in determining anticancer immune responses.
Using flow cytometric and confocal microscopy analyses, Zeng et al. (2006) demonstrated that NYESO1 (CTAG1B; 300156) bound to immature dendritic cells (DCs), macrophages, and monocytes, but not to T cells or B cells. Immunoprecipitation and tandem mass spectrometric analyses showed that CALR was the only DC surface-specific protein that interacted with NYESO1. Anti-CALR inhibited NYESO1 binding on immature DCs and its cross-presentation to CD8 (see 186910)-positive T cells. Surface plasmon resonance analysis showed that NYESO1 bound to CALR, but not to other molecular chaperones. Zeng et al. (2006) proposed that NYESO1 binding to CALR on macrophages and DCs provides a link between NYESO1, the innate immune system, possibly the adaptive immune response against NYESO1.
By overexpression and knockout analyses in HEK293T cells, Zhang et al. (2022) showed that CANX (114217) and CALR decreased ebolavirus entry by selectively downregulating steady-state ebolavirus GP1,2 (EBOV-GP1,2) protein in a cell type-independent manner. In the process of GP1,2 downregulation, CALR was dependent on CANX and PDIA3 (602046), whereas CANX was independent of CALR and PDIA3. Mechanistically, CANX and CALR targeted GP1,2 to autolysosomes for degradation via the ERAD machinery. A ring finger protein, RNF26 (606130), interacted with EBOV-GP1,2 and was involved in downregulation of EBOV-GP1,2, but RNF26 only supported CALR, and not CANX or PDIA3, to downregulate EBOV-GP1,2 in an E3 ubiquitin ligase activity-independent manner. Instead, CANX coopted RNF185 (620096) to interact with EBOV-GP1,2 and polyubiquitinate it on K673 in its cytoplasmic tail via ubiquitin K27 linkage for degradation.
Persson et al. (2002) stated that the CALR gene contains 9 exons and spans 4.2 kb.
By analysis of somatic cell hybrids, McCauliffe et al. (1990) assigned the CALR gene to chromosome 19p. There was perfect concordance with LDLR (606945) but discordance with C3 (120700). Thus, the calreticulin, or RO, locus may be located in the region of chromosome 19pter-p13.2, distal to C3 and near LDLR.
Rooke et al. (1997) mapped the mouse Calr gene to chromosome 8.
Somatic Mutation in Myeloproliferative Neoplasms
Klampfl et al. (2013) identified calreticulin mutations in 78 of 311 (25%) tumor samples from patients with essential thrombocythemia (see 187950), and in 72 of 203 (35%) tumor samples from patients with primary myelofibrosis (254450). Mutations in CALR, JAK2 (147796), and MPL (159530) were mutually exclusive. Among 289 thrombocythemia samples from a combined cohort of patients with nonmutated JAK2 and MPL, 195 (67%) had mutated CALR; among 120 primary myelofibrosis samples from the same cohort, 105 (88%) had mutated CALR. A total of 36 types of insertions or deletions were identified in exon 9 of CALR, all causing a frameshift to the same alternative reading frame and generating a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion (109091.0001) caused cytokine-independent growth in vitro owing to the activation of STAT5 (601511). Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2.
Nangalia et al. (2013) identified somatic CALR mutations in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in no other hematologic cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 basepair frameshift, which would result in a mutant protein with a novel C terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients.
Klampfl et al. (2013) and Nangalia et al. (2013) identified a somatic 52-bp deletion in exon 9 of the CALR gene (1092_1143del) in patients with myeloproliferative neoplasms, including myelofibrosis (254450) and essential thrombocythemia (see 187950). CALR mutations and JAK2 and MPL mutations were mutually exclusive. The 52-bp mutation resulted in frameshift and premature termination (L367fsTer46). Klampfl et al. (2013) identified a total of 36 types of somatic insertion or deletion within exon 9 of CALR, all of which caused a frameshift to the same alternative reading frame and generated a novel C-terminal peptide in the mutant calreticulin. Klampfl et al. (2013) identified insertions or deletions in exon 9 of CALR in 88% of individuals with primary myelofibrosis with nonmutated JAK2 or MPL. The 52-bp deletion accounted for 53% of all cases of mutated CALR among several types of myeloproliferative neoplasm. Overexpression of this mutation resulted in cytokine-independent growth in vitro through the activation of STAT5 (601511). Nangalia et al. (2013) identified 23 patients with myelofibrosis who carried the L367fsTer46 mutation. Overall, Nangalia et al. (2013) identified 19 different somatic CALR mutations, all in exon 9 and all of which generated a +1 frameshift resulting in a mutant protein with a novel C terminal. CALR mutations were present in 18 of 32 patients (56%) with primary myelofibrosis and in 12 of 14 patients (86%) with progression of essential thrombocythemia to myelofibrosis. Neither Klampfl et al. (2013) nor Nangalia et al. (2013) detected CALR mutation in individuals with polycythemia vera.
Boehm, J., Orth, T., Van Nguyen, P., Soling, H. D. Systemic lupus erythematosus is associated with increased auto-antibody titers against calreticulin and grp94, but calreticulin is not the Ro/SS-A antigen. Europ. J. Clin. Invest. 24: 248-257, 1994. [PubMed: 8050453] [Full Text: https://doi.org/10.1111/j.1365-2362.1994.tb01082.x]
Burns, K., Duggan, B., Atkinson, E. A., Famulski, K. S., Nemer, M., Bleackley, R. C., Michalak, M. Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 367: 476-480, 1994. [PubMed: 8107808] [Full Text: https://doi.org/10.1038/367476a0]
Dedhar, S., Rennie, P. S., Shago, M., Hagesteijn, C.-Y. L., Yang, H., Filmus, J., Hawley, R. G., Bruchovsky, N., Cheng, H., Matusik, R. J., Giguere, V. Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367: 480-483, 1994. [PubMed: 8107809] [Full Text: https://doi.org/10.1038/367480a0]
Frank, M. B. Personal Communication. Oklahoma City, Okla. 6/3/1994.
Gardai, S. J., McPhillips, K. A., Frasch, S. C., Janssen, W. J., Starefeldt, A., Murphy-Ullrich, J. E., Bratton, D. L., Oldenborg, P.-A., Michalak, M., Henson, P. M. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123: 321-334, 2005. [PubMed: 16239148] [Full Text: https://doi.org/10.1016/j.cell.2005.08.032]
Itoh, K., Itoh, Y., Frank, M. B. Protein heterogeneity in the human Ro/SSA ribonucleoproteins: the 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. J. Clin. Invest. 87: 177-186, 1991. [PubMed: 1985094] [Full Text: https://doi.org/10.1172/JCI114968]
Klampfl, T., Gisslinger, H., Harutyunyan, A. S., Nivarthi, H., Rumi, E., Milosevic, J. D., Them, N. C. C., Berg, T., Gisslinger, B., Pietra, D., Chen, D., Vladimer, G. I., and 17 others. Somatic mutations of calreticulin in myeloproliferative neoplasms. New Eng. J. Med. 369: 2379-2390, 2013. [PubMed: 24325356] [Full Text: https://doi.org/10.1056/NEJMoa1311347]
McCauliffe, D. P., Lux, F. A., Lieu, T.-S., Sanz, I., Hanke, J., Newkirk, M. M., Bachinski, L. L., Itoh, Y., Siciliano, M. J., Reichlin, M., Sontheimer, R. D., Capra, J. D. Molecular cloning, expression, and chromosome 19 localization of a human Ro/SS-A autoantigen. J. Clin. Invest. 85: 1379-1391, 1990. [PubMed: 2332496] [Full Text: https://doi.org/10.1172/JCI114582]
McCauliffe, D. P., Zappi, E., Lieu, T.-S., Michalak, M., Sontheimer, R. D., Capra, J. D. A human Ro/SS-A autoantigen is the homologue of calreticulin and is highly homologous with onchocercal RAL-1 antigen and an aplysia 'memory molecule.'. J. Clin. Invest. 86: 332-335, 1990. [PubMed: 2365822] [Full Text: https://doi.org/10.1172/JCI114704]
Nangalia, J., Massie, C. E., Baxter, E. J., Nice, F. L., Gundem, G., Wedge, D. C., Avezov, E., Li, J., Kollmann, K., Kent, D. G., Aziz, A., Godfrey, A. L., and 40 others. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New Eng. J. Med. 369: 2391-2405, 2013. [PubMed: 24325359] [Full Text: https://doi.org/10.1056/NEJMoa1312542]
Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J.-L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Metivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., Kroemer, G. Calreticulin exposure dictates immunogenicity of cancer cell death. Nature Med. 13: 54-61, 2007. [PubMed: 17187072] [Full Text: https://doi.org/10.1038/nm1523]
Orr, A. W., Pedraza, C. E., Pallero, M. A., Elzie, C. A., Goicoechea, S., Strickland, D. K., Murphy-Ullrich, J. E. Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly. J. Cell Biol. 161: 1179-1189, 2003. Note: Erratum: J. Cell Biol.: 162: 521 only, 2003. [PubMed: 12821648] [Full Text: https://doi.org/10.1083/jcb.200302069]
Orth, T., Dorner, T., Meyer Zum Buschenfelde, K.-H., Mayet, W.-J. Complete congenital heart block is associated with increased autoantibody titers against calreticulin. Europ. J. Clin. Invest. 26: 205-215, 1996. [PubMed: 8904349] [Full Text: https://doi.org/10.1046/j.1365-2362.1996.120270.x]
Persson, S., Rosenquist, M., Sommarin, M. Identification of a novel calreticulin isoform (Crt2) in human and mouse. Gene 297: 151-158, 2002. [PubMed: 12384296] [Full Text: https://doi.org/10.1016/s0378-1119(02)00880-6]
Rooke, K., Briquet-Laugier, V., Xia, Y.-R., Lusis, A. J., Doolittle, M. H. Mapping of the gene for calreticulin (Calr) to mouse chromosome 8. Mammalian Genome 8: 870-871, 1997. [PubMed: 9337407] [Full Text: https://doi.org/10.1007/s003359900599]
Zeng, G., Aldridge, M. E., Tian, X., Seiler, D., Zhang, X., Jin, Y., Rao, J., Li, W., Chen, D., Langford, M. P., Duggan, C., Belldegrun, A. S., Dubinett, S. M. Dendritic cell surface calreticulin is a receptor for NY-ESO-1: direct interactions between tumor-associated antigen and the innate immune system. J. Immun. 177: 3582-3589, 2006. [PubMed: 16951317] [Full Text: https://doi.org/10.4049/jimmunol.177.6.3582]
Zhang, J., Wang, B., Gao, X., Peng, C., Shan, C., Johnson, S. F., Schwartz, R. C., Zheng, Y. H. RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy. Nature Commun. 13: 6007, 2022. [PubMed: 36224200] [Full Text: https://doi.org/10.1038/s41467-022-33805-9]