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Gene Review

Calr  -  calreticulin

Mus musculus

Synonyms: CRP55, CRT, Calregulin, Calreticulin, ERp60, ...
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Disease relevance of Calr


High impact information on Calr

  • Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte [6].
  • These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal [6].
  • Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice [7].
  • Calreticulin exposure dictates the immunogenicity of cancer cell death [7].
  • We have now developed calreticulin-deficient embryonic stem (ES) cells and isolated embryonic fibroblasts from calreticulin mutant mice [8].

Chemical compound and disease context of Calr


Biological context of Calr

  • Mapping of the gene for calreticulin (Calr) to mouse chromosome 8 [11].
  • Therefore, the aim of this study was to investigate the role of CRT in the regulation of apoptosis via modulating p53 function and expression [12].
  • Calreticulin is a Ca2+ -binding chaperone that resides in the lumen of the endoplasmic reticulum and is involved in the regulation of intracellular Ca2+ homeostasis and in the folding of newly synthesized glycoproteins [13].
  • We conclude that mutation of a single amino acid residue in calreticulin has devastating consequences for its chaperone function, indicating that mutations in chaperones may play a significant role in protein folding disorders [14].
  • The Cys(88) and Cys(120) mutants rescued the calreticulin-deficient phenotype only partially ( approximately 40%), and the Trp(244) and Trp(302) mutants did not rescue it at all [13].

Anatomical context of Calr


Associations of Calr with chemical compounds

  • Although not fully interchangeable during assistance of glycoprotein folding, calreticulin and calnexin may work, independently, as efficient and crucial factors for retention in the ER of nonnative polypeptides [15].
  • Bradykinin-dependent Ca2+ release from the ER was rescued by wild type calreticulin and by the His25, His82, or His128 mutant but not by the His153 mutant [14].
  • Functional relationship between calreticulin, calnexin, and the endoplasmic reticulum luminal domain of calnexin [17].
  • Identification of an N-domain histidine essential for chaperone function in calreticulin [14].
  • Wild type calreticulin and the His25, His82, and His128 mutants all prevented in vitro thermal aggregation of malate dehydrogenase and IgY, whereas the His153 mutant did not, indicating that His153 chaperone function was impaired [14].

Physical interactions of Calr


Regulatory relationships of Calr

  • These results, lead us to conclude that CRT regulates p53 function by affecting its rate of degradation and nuclear localization [12].
  • PERK and Ire1alpha and eIF2alpha are also activated in calreticulin-deficient cells [21].
  • RESULTS: We show here that the levels of N-cadherin are downregulated in calreticulin-deficient mouse embryonic hearts, which may lead to the disarray and wavy appearance of myofibrils in these mice, which we detected at all investigated stages of cardiac development [22].
  • Here, using L fibroblast cell lines expressing different levels of calreticulin, we show that calreticulin plays a role in the control of cell adhesiveness via regulation of expression of vinculin, a cytoskeletal protein essential for cell-substratum and cell-cell attachments [23].
  • Here we show that the transcription factor Nkx2.5 activates expression of the calreticulin gene in the heart [24].

Other interactions of Calr

  • Calreticulin associated more abundantly with orphan calnexin substrates only in infected cells and preferentially with polypeptides of viral origin, showing stronger dependence of model viral glycoproteins on endoplasmic reticulum lectins [25].
  • Here we show a significant decrease in both basal and DNA damage induced p53 functions in the CRT-deficient cells (crt-/-) [12].
  • We identified four amino acid residues (Glu(239), Asp(241), Glu(243), and Trp(244)) at the hairpin tip of the P-domain that are critical in the formation of a complex between ERp57 and calreticulin [13].
  • On the cell surface, GRP78, PDI and Crt associate with other proteins and form complexes of different sizes [26].
  • Using a Drosophila expression system and the mouse class I histocompatibility molecule as a model glycoprotein, we found that calreticulin does possess apparent chaperone and quality control functions, enhancing class I folding and subunit assembly, stabilizing subunits, and impeding export of assembly intermediates from the ER [17].

Analytical, diagnostic and therapeutic context of Calr


  1. Soluble tyrosinase is an endoplasmic reticulum (ER)-associated degradation substrate retained in the ER by calreticulin and BiP/GRP78 and not calnexin. Popescu, C.I., Paduraru, C., Dwek, R.A., Petrescu, S.M. J. Biol. Chem. (2005) [Pubmed]
  2. Complete heart block and sudden death in mice overexpressing calreticulin. Nakamura, K., Robertson, M., Liu, G., Dickie, P., Nakamura, K., Guo, J.Q., Duff, H.J., Opas, M., Kavanagh, K., Michalak, M. J. Clin. Invest. (2001) [Pubmed]
  3. Calreticulin is essential for cardiac development. Mesaeli, N., Nakamura, K., Zvaritch, E., Dickie, P., Dziak, E., Krause, K.H., Opas, M., MacLennan, D.H., Michalak, M. J. Cell Biol. (1999) [Pubmed]
  4. Enhancement of DNA vaccine potency by coadministration of a tumor antigen gene and DNA encoding serine protease inhibitor-6. Kim, T.W., Hung, C.F., Boyd, D.A., He, L., Lin, C.T., Kaiserman, D., Bird, P.I., Wu, T.C. Cancer Res. (2004) [Pubmed]
  5. Calreticulin displays in vivo peptide-binding activity and can elicit CTL responses against bound peptides. Nair, S., Wearsch, P.A., Mitchell, D.A., Wassenberg, J.J., Gilboa, E., Nicchitta, C.V. J. Immunol. (1999) [Pubmed]
  6. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. 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 (2005) [Pubmed]
  7. 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]
  8. Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion. Coppolino, M.G., Woodside, M.J., Demaurex, N., Grinstein, S., St-Arnaud, R., Dedhar, S. Nature (1997) [Pubmed]
  9. Inhibition of retinoic acid receptor function and retinoic acid-regulated gene expression in mouse melanoma cells by calreticulin. A potential pathway for cyclic AMP regulation of retinoid action. Desai, D., Michalak, M., Singh, N.K., Niles, R.M. J. Biol. Chem. (1996) [Pubmed]
  10. Calreticulin-integrin bidirectional signaling complex. Zhu, Q., Zelinka, P., White, T., Tanzer, M.L. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  11. Mapping of the gene for calreticulin (Calr) to mouse chromosome 8. Rooke, K., Briquet-Laugier, V., Xia, Y.R., Lusis, A.J., Doolittle, M.H. Mamm. Genome (1997) [Pubmed]
  12. Impaired p53 expression, function, and nuclear localization in calreticulin-deficient cells. Mesaeli, N., Phillipson, C. Mol. Biol. Cell (2004) [Pubmed]
  13. Identification by mutational analysis of amino acid residues essential in the chaperone function of calreticulin. Martin, V., Groenendyk, J., Steiner, S.S., Guo, L., Dabrowska, M., Parker, J.M., Müller-Esterl, W., Opas, M., Michalak, M. J. Biol. Chem. (2006) [Pubmed]
  14. Identification of an N-domain histidine essential for chaperone function in calreticulin. Guo, L., Groenendyk, J., Papp, S., Dabrowska, M., Knoblach, B., Kay, C., Parker, J.M., Opas, M., Michalak, M. J. Biol. Chem. (2003) [Pubmed]
  15. Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. Molinari, M., Eriksson, K.K., Calanca, V., Galli, C., Cresswell, P., Michalak, M., Helenius, A. Mol. Cell (2004) [Pubmed]
  16. Identification of a novel calreticulin isoform (Crt2) in human and mouse. Persson, S., Rosenquist, M., Sommarin, M. Gene (2002) [Pubmed]
  17. Functional relationship between calreticulin, calnexin, and the endoplasmic reticulum luminal domain of calnexin. Danilczyk, U.G., Cohen-Doyle, M.F., Williams, D.B. J. Biol. Chem. (2000) [Pubmed]
  18. Modulation of the retinoic acid and retinoid X receptor signaling pathways in P19 embryonal carcinoma cells by calreticulin. Shago, M., Flock, G., Leung Hagesteijn, C.Y., Woodside, M., Grinstein, S., Giguère, V., Dedhar, S. Exp. Cell Res. (1997) [Pubmed]
  19. Physical association of the K3 protein of gamma-2 herpesvirus 68 with major histocompatibility complex class I molecules with impaired peptide and beta(2)-microglobulin assembly. Yu, Y.Y., Harris, M.R., Lybarger, L., Kimpler, L.A., Myers, N.B., Virgin, H.W., Hansen, T.H. J. Virol. (2002) [Pubmed]
  20. Immunogenicity of calreticulin-bound murine leukemia virus glycoprotein gp90. Mimura, Y., Golgher, D., Mimura-Kimura, Y., Dwek, R.A., Rudd, P.M., Elliott, T. Adv. Exp. Med. Biol. (2005) [Pubmed]
  21. Compromised calnexin function in calreticulin-deficient cells. Knee, R., Ahsan, I., Mesaeli, N., Kaufman, R.J., Michalak, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  22. Ultrastructural analysis of development of myocardium in calreticulin-deficient mice. Lozyk, M.D., Papp, S., Zhang, X., Nakamura, K., Michalak, M., Opas, M. BMC Dev. Biol. (2006) [Pubmed]
  23. Calreticulin modulates cell adhesiveness via regulation of vinculin expression. Opas, M., Szewczenko-Pawlikowski, M., Jass, G.K., Mesaeli, N., Michalak, M. J. Cell Biol. (1996) [Pubmed]
  24. COUP-TF1 antagonizes Nkx2.5-mediated activation of the calreticulin gene during cardiac development. Guo, L., Lynch, J., Nakamura, K., Fliegel, L., Kasahara, H., Izumo, S., Komuro, I., Agellon, L.B., Michalak, M. J. Biol. Chem. (2001) [Pubmed]
  25. The use of calnexin and calreticulin by cellular and viral glycoproteins. Pieren, M., Galli, C., Denzel, A., Molinari, M. J. Biol. Chem. (2005) [Pubmed]
  26. KDEL proteins are found on the surface of NG108-15 cells. Xiao, G., Chung, T.F., Pyun, H.Y., Fine, R.E., Johnson, R.J. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  27. Role of calnexin, calreticulin, and endoplasmic reticulum mannosidase I in apolipoprotein(a) intracellular targeting. Wang, J., White, A.L. Biochemistry (2000) [Pubmed]
  28. The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. Dupuis, M., Schaerer, E., Krause, K.H., Tschopp, J. J. Exp. Med. (1993) [Pubmed]
  29. Molecular cloning and expression of SmIrV1, a Schistosoma mansoni antigen with similarity to calnexin, calreticulin, and OvRal1. Hawn, T.R., Tom, T.D., Strand, M. J. Biol. Chem. (1993) [Pubmed]
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