PDB rendering based on 1hhn.
|Symbols||; CRT; HEL-S-99n; RO; SSA; cC1qR|
|RNA expression pattern|
Calreticulin is a multifunctional protein that binds Ca2+ ions (a second messenger in signal transduction), rendering it inactive. The Ca2+ is bound with low affinity, but high capacity, and can be released on a signal (see inositol triphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum.
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.
In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocytosis and primary myelofibrosis, which makes CALR mutations the second most common in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon, generating a reading frame shift of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum KDEL retention signal. 
Role in cancer
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.
- McCauliffe DP, Zappi E, Lieu TS, Michalak M, Sontheimer RD, Capra JD; Zappi; Lieu; Michalak; Sontheimer; Capra (July 1990). """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 (1): 332–5.
- "Entrez Gene: calreticulin".
- Mobilferrin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Beutler E, West C, Gelbart T; West; Gelbart (1997). "HLA-H and associated proteins in patients with hemochromatosis". Mol. Med. 3 (6): 397–402.
- Michalak M, Lynch J, Groenendyk J, Guo L, Robert Parker JM, Opas M; Lynch; Groenendyk; Guo; Robert Parker; Opas (November 2002). "Calreticulin in cardiac development and pathology". Biochim. Biophys. Acta 1600 (1–2): 32–7.
- "Entrez Gene: CALR calreticulin".
- 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; Massie; Baxter; Nice; Gundem; Wedge; Avezov; Li; Kollmann; Kent; Aziz; Godfrey; Hinton; Martincorena; Van Loo; Jones; Guglielmelli; Tarpey; Harding; Fitzpatrick; Goudie; Ortmann; Loughran; Raine; Jones; Butler; Teague; O'Meara; McLaren et al. (December 2013). "Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2". N Engl J Med 369 (25): 2391–405.
- 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; Gisslinger; Harutyunyan; Nivarthi; Rumi; Milosevic; Them; Berg; Gisslinger; Pietra; Chen; Vladimer; Bagienski; Milanesi; Casetti; Sant'Antonio; Ferretti; Elena; Schischlik; Cleary; Six; Schalling; Schönegger; Bock; Malcovati; Pascutto; Superti-Furga; Cazzola; Kralovics (December 2013). "Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms". N Engl J Med 369 (25): 2379–90.
- 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; Jaiswal; Weissman-Tsukamoto; Alizadeh; Gentles; Volkmer; Weiskopf; Willingham; Raveh; Park; Majeti; Weissman (December 2010). "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47". Sci Transl Med 2 (63): 63ra94.
- 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.
- 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.
- Del Bem LEV (2011). "The evolutionary history of calreticulin and calnexin genes in green plants". Genetica 139 (2): 225–9.
- Coppolino MG, Dedhar S; Dedhar (1998). "Calreticulin". Int. J. Biochem. Cell Biol. 30 (5): 553–8.
- Brucato A, Grava C, Bortolati M et al. (2009). "Congenital Heart Block Not Associated with Anti-Ro/La Antibodies: Comparison with Anti-Ro/La-positive Cases". J. Rheumatol. 36 (8): 1744–8.
- Peng RQ, Chen YB, Ding Y et al. (2010). "Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer". World J. Gastroenterol. 16 (19): 2428–34.
- Tarr JM, Young PJ, Morse R et al. (2010). "A mechanism of release of calreticulin from cells during apoptosis". J. Mol. Biol. 401 (5): 799–812.
- Abd Alla J, Reeck K, Langer A et al. (2009). "Calreticulin enhances B2 bradykinin receptor maturation and heterodimerization". Biochem. Biophys. Res. Commun. 387 (1): 186–90.
- Caramelo JJ, Parodi AJ; Parodi (2008). "Getting In and Out from Calnexin/Calreticulin Cycles". J. Biol. Chem. 283 (16): 10221–5.
- 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". Oncogene 28 (42): 3714–22.
- Gelebart P, Opas M, Michalak M; Opas; Michalak (2005). "Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum". Int. J. Biochem. Cell Biol. 37 (2): 260–6.
- Qiu Y, Michalak M; Michalak (2009). "Transcriptional control of the calreticulin gene in health and disease". Int. J. Biochem. Cell Biol. 41 (3): 531–8.
- Zhu Y, Zhang W, Veerapen N et al. (2010). "Calreticulin Controls the Rate of Assembly of CD1d Molecules in the Endoplasmic Reticulum". J. Biol. Chem. 285 (49): 38283–92.
- Talmud PJ, Drenos F, Shah S et al. (2009). "Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip". Am. J. Hum. Genet. 85 (5): 628–42.
- Taner SB, Pando MJ, Roberts A et al. (2011). "Interactions of NK cell receptor KIR3DL1*004 with chaperones and conformation-specific antibody reveal a functional folded state as well as predominant intracellular retention". J. Immunol. 186 (1): 62–72.
- 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.
- 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 Cycle 9 (15): 3072–7.
- Sato H, Azuma Y, Higai K, Matsumoto K; Azuma; Higai; Matsumoto (2009). "Altered expression of glycoproteins on the cell surface of Jurkat cells during etoposide-induced apoptosis: shedding and intracellular translocation of glycoproteins". Biochim. Biophys. Acta 1790 (10): 1198–205.
- 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.
- Alur M, Nguyen MM, Eggener SE et al. (2009). "Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis". Am. J. Pathol. 175 (2): 882–90.
- Bailey SD, Xie C, Do R et al. (2010). "Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study". Diabetes Care 33 (10): 2250–3.
- 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.
- 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.
- Calreticulin at the US National Library of Medicine Medical Subject Headings (MeSH)