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Gene Review

CALR  -  calreticulin

Homo sapiens

Synonyms: CRP55, CRT, CRTC, Calregulin, Calreticulin, ...
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Disease relevance of CALR

  • Nonglycosylated HIV envelope protein was not associated with calreticulin, suggesting a requirement for N-linked oligosaccharides on newly synthesized proteins as has been reported for calnexin [1].
  • Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells [2].
  • Complete congenital heart block is associated with increased autoantibody titers against calreticulin [3].
  • Accordingly, quantitative immunoblot analysis showed that Calreticulin expression was significantly lower in human colonic cancer cell lines than in preparations of isolated human normal colonic epithelial cells [4].
  • Recent studies, based on proteomic approaches on whole tissue samples containing both neoplastic and non-neoplastic cells, have shown alterations of Calreticulin expression in colon carcinomas, albeit with divergent results [4].

Psychiatry related information on CALR


High impact information on CALR

  • Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation [10].
  • Further deglucosylation of the oligosaccharides by glucosidase II liberates glycoproteins from their calnexin/calreticulin anchors [11].
  • Calreticulin exposure dictates the immunogenicity of cancer cell death [12].
  • Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice [12].
  • Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation [13].

Chemical compound and disease context of CALR


Biological context of CALR


Anatomical context of CALR


Associations of CALR with chemical compounds

  • Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP [25].
  • An inhibitor of glucose trimming, castanospermine (CST), abolished binding to Cnx/Crt but also unexpectedly accelerated receptor homodimerization resulting in misfolded oligomeric proreceptors whose processing was delayed and cell surface expression was also decreased by approximately 30% [19].
  • CRT defines a new export pathway that may regulate the transcriptional activity of steroid hormone receptors [18].
  • The data are consistent with a model in which the release of peptide-loaded major histocompatibility complex class I molecules from calreticulin, induced by deglucosylation of the heavy chain N-linked glycan, signals the dissociation of the complex [26].
  • Nonglycosylated MPO precursors synthesized in the presence of tunicamycin did not interact with CRT [27].

Physical interactions of CALR

  • In addition, we report that ERp27 is bound by ERp57 both in vitro and in vivo by a similar mechanism by which ERp57 binds calreticulin [28].
  • Peptides spanning aa 19-36 (RWIESKHKSDFGKFVLSS) blocked hep I-stimulated focal adhesion disassembly, indicating that the TSP/hep I-binding site is located to this sequence in calreticulin [29].
  • Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell [30].
  • We show that APP binds transiently to Crt in a manner that is pH, divalent cation, and N-linked glycosylation-dependent [31].
  • Calreticulin is an endoplasmic reticulum luminal calcium-binding chaperone involved in various cellular functions and is a ligand for the scavenger receptor CD91 [4].

Co-localisations of CALR


Regulatory relationships of CALR


Other interactions of CALR

  • Here, we show that the related chaperone, calreticulin, binds human class I-beta 2m dimers prior to peptide loading [25].
  • Together, these studies demonstrate a chaperone function for Cnx/Crt in HIR folding in vivo and also provide evidence that folding efficiency and homodimerization are counterbalanced [19].
  • Heavy chains were also isolated from Raji cells in multimolecular complexes (peptide loading complexes) containing the transporter associated with antigen processing, tapasin and ERp57 with and without the lectin-like folding chaperone, calreticulin [26].
  • The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters [37].
  • Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin [24].

Analytical, diagnostic and therapeutic context of CALR


  1. Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin. Otteken, A., Moss, B. J. Biol. Chem. (1996) [Pubmed]
  2. Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells. McCool, D.J., Okada, Y., Forstner, J.F., Forstner, G.G. Biochem. J. (1999) [Pubmed]
  3. Complete congenital heart block is associated with increased autoantibody titers against calreticulin. Orth, T., Dorner, T., Meyer Zum Buschenfelde, K.H., Mayet, W.J. Eur. J. Clin. Invest. (1996) [Pubmed]
  4. Altered Calreticulin expression in human colon cancer: Maintenance of Calreticulin expression is associated with mucinous differentiation. Toquet, C., Jarry, A., Bou-Hanna, C., Bach, K., Denis, M.G., Mosnier, J.F., Laboisse, C.L. Oncol. Rep. (2007) [Pubmed]
  5. Different expression of calreticulin and immunoglobulin binding protein in Alzheimer's disease brain. Taguchi, J., Fujii, A., Fujino, Y., Tsujioka, Y., Takahashi, M., Tsuboi, Y., Wada, I., Yamada, T. Acta Neuropathol. (2000) [Pubmed]
  6. Iron-induced oxidative stress up-regulates calreticulin levels in intestinal epithelial (Caco-2) cells. Núñez, M.T., Osorio, A., Tapia, V., Vergara, A., Mura, C.V. J. Cell. Biochem. (2001) [Pubmed]
  7. Interplay of four idiotypes and interaction with autoantibodies in lupus patients, their relatives and their spouses. Youinou, P., Isenberg, D.A., Kalsi, J.K., Dugoujon, J.M., Ravirajan, C.T., Muller, S., Blanco, F., Piette, J.C., Guillevin, L., Jouquan, J., Semana, G., Salmon, D., Shoenfeld, Y., Bach, J.F. J. Autoimmun. (1996) [Pubmed]
  8. Insomnia related to dysthymia: polysomnographic and psychometric comparison with normal controls and acute therapeutic trials with trazodone. Saletu-Zyhlarz, G.M., Abu-Bakr, M.H., Anderer, P., Semler, B., Decker, K., Parapatics, S., Tschida, U., Winkler, A., Saletu, B. Neuropsychobiology (2001) [Pubmed]
  9. P300 and slow wave: the effects of reaction time quartile. Friedman, D. Biological psychology. (1984) [Pubmed]
  10. Roles of N-linked glycans in the endoplasmic reticulum. Helenius, A., Aebi, M. Annu. Rev. Biochem. (2004) [Pubmed]
  11. Protein glucosylation and its role in protein folding. Parodi, A.J. Annu. Rev. Biochem. (2000) [Pubmed]
  12. Calreticulin exposure dictates the immunogenicity of cancer cell death. Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G.M., Apetoh, L., Perfettini, J.L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., M??tivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., Kroemer, G. Nat. Med. (2007) [Pubmed]
  13. Inhibition of nuclear hormone receptor activity by calreticulin. Dedhar, S., Rennie, P.S., Shago, M., Hagesteijn, C.Y., Yang, H., Filmus, J., Hawley, R.G., Bruchovsky, N., Cheng, H., Matusik, R.J. Nature (1994) [Pubmed]
  14. Insights into the quaternary association of proteins through structure graphs: a case study of lectins. Brinda, K.V., Surolia, A., Vishveshwara, S. Biochem. J. (2005) [Pubmed]
  15. Increased oxidative metabolism in phytohemagglutinin-stimulated lymphocytes from patients with systemic lupus erythematosus is associated with serum SSA antibody. Benke, P.J., Drisko, J., Ahmad, P. Biochem. Med. Metab. Biol. (1991) [Pubmed]
  16. Calreticulin expression is associated with androgen regulation of the sensitivity to calcium ionophore-induced apoptosis in LNCaP prostate cancer cells. Zhu, N., Wang, Z. Cancer Res. (1999) [Pubmed]
  17. Homozygous C2 deficiency, lupus erythematosus, and anti-Ro (SSA) antibodies. Provost, T.T., Arnett, F.C., Reichlin, M. Arthritis Rheum. (1983) [Pubmed]
  18. Calreticulin Is a receptor for nuclear export. Holaska, J.M., Black, B.E., Love, D.C., Hanover, J.A., Leszyk, J., Paschal, B.M. J. Cell Biol. (2001) [Pubmed]
  19. Folding of insulin receptor monomers is facilitated by the molecular chaperones calnexin and calreticulin and impaired by rapid dimerization. Bass, J., Chiu, G., Argon, Y., Steiner, D.F. J. Cell Biol. (1998) [Pubmed]
  20. Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria. Arnaudeau, S., Frieden, M., Nakamura, K., Castelbou, C., Michalak, M., Demaurex, N. J. Biol. Chem. (2002) [Pubmed]
  21. Ca2+-dependent redox modulation of SERCA 2b by ERp57. Li, Y., Camacho, P. J. Cell Biol. (2004) [Pubmed]
  22. Calreticulin is at the surface of circulating neutrophils and uses CD59 as an adaptor molecule. Ghiran, I., Klickstein, L.B., Nicholson-Weller, A. J. Biol. Chem. (2003) [Pubmed]
  23. Prominence of beta 2-microglobulin, class I heavy chain conformation, and tapasin in the interactions of class I heavy chain with calreticulin and the transporter associated with antigen processing. Solheim, J.C., Harris, M.R., Kindle, C.S., Hansen, T.H. J. Immunol. (1997) [Pubmed]
  24. Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin. Goicoechea, S., Orr, A.W., Pallero, M.A., Eggleton, P., Murphy-Ullrich, J.E. J. Biol. Chem. (2000) [Pubmed]
  25. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Sadasivan, B., Lehner, P.J., Ortmann, B., Spies, T., Cresswell, P. Immunity (1996) [Pubmed]
  26. Identification of specific glycoforms of major histocompatibility complex class I heavy chains suggests that class I peptide loading is an adaptation of the quality control pathway involving calreticulin and ERp57. Radcliffe, C.M., Diedrich, G., Harvey, D.J., Dwek, R.A., Cresswell, P., Rudd, P.M. J. Biol. Chem. (2002) [Pubmed]
  27. Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase. Nauseef, W.M., McCormick, S.J., Clark, R.A. J. Biol. Chem. (1995) [Pubmed]
  28. ERp27, a New Non-catalytic Endoplasmic Reticulum-located Human Protein Disulfide Isomerase Family Member, Interacts with ERp57. Alanen, H.I., Williamson, R.A., Howard, M.J., Hatahet, F.S., Salo, K.E., Kauppila, A., Kellokumpu, S., Ruddock, L.W. J. Biol. Chem. (2006) [Pubmed]
  29. The anti-adhesive activity of thrombospondin is mediated by the N-terminal domain of cell surface calreticulin. Goicoechea, S., Pallero, M.A., Eggleton, P., Michalak, M., Murphy-Ullrich, J.E. J. Biol. Chem. (2002) [Pubmed]
  30. Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain. Perrone, L., Tell, G., Di Lauro, R. J. Biol. Chem. (1999) [Pubmed]
  31. Calreticulin functions as a molecular chaperone for the beta-amyloid precursor protein. Johnson, R.J., Xiao, G., Shanmugaratnam, J., Fine, R.E. Neurobiol. Aging (2001) [Pubmed]
  32. NOX2 and NOX4 Mediate Proliferative Response in Endothelial Cells. Petry, A., Djordjevic, T., Weitnauer, M., Kietzmann, T., Hess, J., Görlach, A. Antioxid. Redox Signal. (2006) [Pubmed]
  33. Co-localization of calcium-modulating cyclophilin ligand with intracellular calcium pools. Holloway, M.P., Bram, R.J. J. Biol. Chem. (1998) [Pubmed]
  34. Calreticulin promotes folding/dimerization of human lipoprotein lipase expressed in insect cells (sf21). Zhang, L., Wu, G., Tate, C.G., Lookene, A., Olivecrona, G. J. Biol. Chem. (2003) [Pubmed]
  35. Ribonuclease activity and RNA binding of recombinant human Dicer. Provost, P., Dishart, D., Doucet, J., Frendewey, D., Samuelsson, B., Rådmark, O. EMBO J. (2002) [Pubmed]
  36. Calreticulin Represses E-cadherin Gene Expression in Madin-Darby Canine Kidney Cells via Slug. Hayashida, Y., Urata, Y., Muroi, E., Kono, T., Miyata, Y., Nomata, K., Kanetake, H., Kondo, T., Ihara, Y. J. Biol. Chem. (2006) [Pubmed]
  37. The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters. McCauliffe, D.P., Yang, Y.S., Wilson, J., Sontheimer, R.D., Capra, J.D. J. Biol. Chem. (1992) [Pubmed]
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