A similar quality-control chaperone, calnexin, performs the same service for soluble proteins as does calreticulin. Both proteins, calnexin and calreticulin, have the function of binding to oligosaccharides containing terminal glucose residues, thereby targeting them for degradation. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the RER will re-add glucose residues so that other calreticulin/calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.
Studies on transgenic mice reveal that calreticulin is a cardiac embryonic gene that is essential during development.
Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. 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. 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. 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.
Calreticulin binds to antibodies in certain sera of systemic lupus and Sjogren patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM classes.
Calreticulin (CRT) is expressed in many cancer cells and plays a role to promote macrophages to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed is the presence of another molecule with signal CD47, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.
^Michalak M, Lynch J, Groenendyk J, Guo L, Robert Parker JM, Opas M (November 2002). "Calreticulin in cardiac development and pathology". Biochim. Biophys. Acta1600 (1–2): 32–7. doi:10.1016/S1570-9639(02)00441-7. PMID12445456.
^Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (December 2013). "Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2". N Engl J Med. doi:10.1056/NEJMoa1312542. PMID24325359.
^Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (December 2013). "Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms". N Engl J Med. doi:10.1056/NEJMoa1311347. PMID24325356.
^Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R, Weissman IL (December 2010). "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47". Sci Transl Med2 (63): 63ra94. doi:10.1126/scitranslmed.3001375. PMID21178137. Lay summary – Stanford School of Medicine.
^Andrin, C; Pinkoski M J, Burns K, Atkinson E A, Krahenbuhl O, Hudig D, Fraser S A, Winkler U, Tschopp J, Opas M, Bleackley R C, Michalak M (Jul 1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry (UNITED STATES) 37 (29): 10386–94. doi:10.1021/bi980595z. ISSN0006-2960. PMID9671507.Cite uses deprecated parameters (help)
^Perrone, L; Tell G, Di Lauro R (Feb 1999). "Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain". J. Biol. Chem. (UNITED STATES) 274 (8): 4640–5. doi:10.1074/jbc.274.8.4640. ISSN0021-9258. PMID9988700.Cite uses deprecated parameters (help)
Du XL, Yang H, Liu SG et al. (2009). "Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma". Oncogene28 (42): 3714–22. doi:10.1038/onc.2009.237. PMID19684620.
Tarr JM, Winyard PG, Ryan B et al. (2010). "Extracellular calreticulin is present in the joints of patients with rheumatoid arthritis and inhibits FasL (CD95L)-mediated apoptosis of T cells". Arthritis Rheum.62 (10): 2919–29. doi:10.1002/art.27602. PMID20533543.
Kepp O, Gdoura A, Martins I et al. (2010). "Lysyl tRNA synthetase is required for the translocation of calreticulin to the cell surface in immunogenic death". Cell Cycle9 (15): 3072–7. doi:10.4161/cc.9.15.12459. PMID20699648.
Sato H, Azuma Y, Higai K, Matsumoto K (2009). "Altered expression of glycoproteins on the cell surface of Jurkat cells during etoposide-induced apoptosis: shedding and intracellular translocation of glycoproteins". Biochim. Biophys. Acta1790 (10): 1198–205. doi:10.1016/j.bbagen.2009.05.019. PMID19524015.
Hong C, Qiu X, Li Y et al. (2010). "Functional analysis of recombinant calreticulin fragment 39-272: implications for immunobiological activities of calreticulin in health and disease". J. Immunol.185 (8): 4561–9. doi:10.4049/jimmunol.1000536. PMID20855873.
Nabi MO, Mirabzadeh A, Feizzadeh G et al. (2010). "Novel mutations in the calreticulin gene core promoter and coding sequence in schizoaffective disorder". Am. J. Med. Genet. B Neuropsychiatr. Genet.153B (2): 706–9. doi:10.1002/ajmg.b.31036. PMID19760677.
Schardt JA, Eyholzer M, Timchenko NA et al. (2010). "Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia". J. Cell. Mol. Med.14 (6B): 1509–19. doi:10.1111/j.1582-4934.2009.00870.x. PMID19659458.