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Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene.^[1]^[2]

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.^[2]

The term "Mobilferrin"^[3] is considered to be the same as calreticulin by some sources.^[4]

Function

Calreticulin binds to misfolded proteins and prevents them from being exported from the endoplasmic reticulum to the Golgi apparatus.

A similar quality-control molecular 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.^[5]

Calreticulin and calnexin are also integral proteins in the production of MHC class I Proteins. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.^[6] After the β2-microglobulin binds to the peptide-loading complex (PLC), calreticulin (along with ERp57 takes over the job of chaperoning the MHC class I protein while the tapasin links the complex to the transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.

Transcription regulation

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.

Clinical significance

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.^[7]

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.^[8]^[9]

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.^[10]

Interactions

Calreticulin has been shown to interact with Perforin^[11] and NK2 homeobox 1.^[12]

References

^ McCauliffe DP, Zappi E, Lieu TS, Michalak M, Sontheimer RD, Capra JD (Jul 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"". The Journal of Clinical Investigation 86 (1): 332–5. doi:10.1172/JCI114704. PMC 296725. PMID 2365822.
^ ^a ^b "Entrez Gene: calreticulin".
^ Mobilferrin at the US National Library of Medicine Medical Subject Headings (MeSH)
^ Beutler E, West C, Gelbart T (Jun 1997). "HLA-H and associated proteins in patients with hemochromatosis". Molecular Medicine (Cambridge, Mass.) 3 (6): 397–402. PMC 2230203. PMID 9234244.
^ Michalak M, Lynch J, Groenendyk J, Guo L, Robert Parker JM, Opas M (Nov 2002). "Calreticulin in cardiac development and pathology". Biochimica Et Biophysica Acta 1600 (1-2): 32–7. doi:10.1016/S1570-9639(02)00441-7. PMID 12445456.
^ Murphy K (2011). Janeway's Immunobiology (8th ed.). Oxford: Taylor & Francis. ISBN 978-0815342434.
^ "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 (Dec 2013). "Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2". The New England Journal of Medicine 369 (25): 2391–405. doi:10.1056/NEJMoa1312542. PMC 3966280. PMID 24325359.
^ 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 (Dec 2013). "Somatic mutations of calreticulin in myeloproliferative neoplasms". The New England Journal of Medicine 369 (25): 2379–90. doi:10.1056/NEJMoa1311347. PMID 24325356.
^ 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 (Dec 2010). "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47". Science Translational Medicine 2 (63): 63ra94. doi:10.1126/scitranslmed.3001375. PMC 4126904. PMID 21178137. Lay summary – Stanford School of Medicine.
^ Andrin C, Pinkoski MJ, Burns K, Atkinson EA, Krahenbuhl O, Hudig D, Fraser SA, Winkler U, Tschopp J, Opas M, Bleackley RC, Michalak M (Jul 1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry 37 (29): 10386–94. doi:10.1021/bi980595z. PMID 9671507.
^ Perrone L, Tell G, Di Lauro R (Feb 1999). "Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain". The Journal of Biological Chemistry 274 (8): 4640–5. doi:10.1074/jbc.274.8.4640. PMID 9988700.

External links

Calreticulin at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 骨髄増殖性腫瘍の概要 overview of the myeloproliferative neoplasms
2. 本態性血小板血症の診断および臨床症状 diagnosis and clinical manifestations of essential thrombocythemia
3. 原発性骨髄線維症における病態 pathogenetic mechanisms in primary myelofibrosis
4. 血小板増加症患者に対するアプローチ approach to the patient with thrombocytosis
5. 原発性骨髄線維症の予後および治療 prognosis and treatment of primary myelofibrosis

English Journal

Molecular cloning and transcriptional activity of a new Petunia calreticulin gene involved in pistil transmitting tract maturation, progamic phase, and double fertilization.

Lenartowski R, Suwińska A, Prusińska J, Gumowski K, Lenartowska M.Author information Laboratory of Isotope and Instrumental Analysis, Faculty of Biology and Environment Protection, Nicolaus Copernicus University, Toruń, Poland, rlenart@umk.pl.AbstractCalreticulin (CRT) is a highly conserved and ubiquitously expressed Ca(2+)-binding protein in multicellular eukaryotes. As an endoplasmic reticulum-resident protein, CRT plays a key role in many cellular processes including Ca(2+) storage and release, protein synthesis, and molecular chaperoning in both animals and plants. CRT has long been suggested to play a role in plant sexual reproduction. To begin to address this possibility, we cloned and characterized the full-length cDNA of a new CRT gene (PhCRT) from Petunia. The deduced amino acid sequence of PhCRT shares homology with other known plant CRTs, and phylogenetic analysis indicates that the PhCRT cDNA clone belongs to the CRT1/CRT2 subclass. Northern blot analysis and fluorescent in situ hybridization were used to assess PhCRT gene expression in different parts of the pistil before pollination, during subsequent stages of the progamic phase, and at fertilization. The highest level of PhCRT mRNA was detected in the stigma-style part of the unpollinated pistil 1 day before anthesis and during the early stage of the progamic phase, when pollen is germinated and tubes outgrow on the stigma. In the ovary, PhCRT mRNA was most abundant after pollination and reached maximum at the late stage of the progamic phase, when pollen tubes grow into the ovules and fertilization occurs. PhCRT mRNA transcripts were seen to accumulate predominantly in transmitting tract cells of maturing and receptive stigma, in germinated pollen/growing tubes, and at the micropylar region of the ovule, where the female gametophyte is located. From these results, we suggest that PhCRT gene expression is up-regulated during secretory activity of the pistil transmitting tract cells, pollen germination and outgrowth of the tubes, and then during gamete fusion and early embryogenesis.
Planta.Planta.2014 Feb;239(2):437-54. doi: 10.1007/s00425-013-1971-4. Epub 2013 Nov 12.
Calreticulin (CRT) is a highly conserved and ubiquitously expressed Ca(2+)-binding protein in multicellular eukaryotes. As an endoplasmic reticulum-resident protein, CRT plays a key role in many cellular processes including Ca(2+) storage and release, protein synthesis, and molecular chaperoning in
PMID 24213153

Low rate of calreticulin mutations in refractory anaemia with ring sideroblasts and marked thrombocytosis.

Broséus J1, Lippert E2, Klampfl T3, Jeromin S4, Zipperer E5, Florensa L6, Harutyunyan AS3, Milosevic JD3, Haferlach T4, Germing U5, Luño E7, Schnittger S4, Kralovics R3, Girodon F8.
Leukemia.Leukemia.2014 Jan 30. doi: 10.1038/leu.2014.49. [Epub ahead of print]
PMID 24476766

Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms.

Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, Girsberger S, Lehmann T, Passweg J, Stern M, Beisel C, Kralovics R, Skoda RC.Author information Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;AbstractMyeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency towards leukemic transformation. We used targeted next generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patients and followed clonal evolution and the impact on clinical outcome. Mutations in calreticulin (CALR) were detected using a sensitive allele-specific PCR. We observed somatic mutations in 90% of patients, and 37% carried somatic mutations other than JAK2-V617F and CALR. The presence of 2 or more somatic mutations significantly reduced overall survival and increased the risk of transformation into acute myeloid leukemia (AML). In particular, somatic mutations with loss of heterozygosity in TP53 were strongly associated with leukemic transformation. We used NGS to follow and quantitate somatic mutations in serial samples from MPN patients. Surprisingly, the number of mutations between early and late patient samples did not significantly change and during a total follow-up of 133 patient years only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low. Our data shows that comprehensive mutational screening at diagnosis and during follow-up has considerable potential to identify patients at high risk of disease progression.
Blood.Blood.2014 Jan 29. [Epub ahead of print]
Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency towards leukemic transformation. We used targeted next generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patie
PMID 24478400

Japanese Journal

Some fine-structural findings on the thyroid gland in Apc^<1638T/1638T> mice that express a C-terminus lacking truncated Apc

YOKOYAMA Atsushi,NOMURA Ryuji,KUROSUMI Masafumi,SHIMOMURA Atsushi,ONOUCHI Takanori,IIZUKA KOGO Akiko,SMITS Ron,FODDE Riccardo,ITOH Mitsuyasu,SENDA Takao
Medical molecular morphology : official journal of the Japanese Society for Clinical Molecular Morphology 45(3), 161-167, 2012-09-01
NAID 10031073930

Calreticulin as a hydrophilic chimeric molecular adjuvant enhances IgG responses to the spike protein of severe acute respiratory syndrome coronavirus

Qiu Xiang,Hong Chao,Li Yue [他]
Microbiology and immunology 56(8), 554-561, 2012-08
NAID 40019376824

Calreticulin Inhibits Prion Protein PrP-(23-98) Aggregation in Vitro

Shiraishi Noriyuki,Inai Yoko,Hirano Yoshiaki [他],IHARA Yoshito
Bioscience, biotechnology, and biochemistry 75(8), 1625-1627, 2011-08-23
… Because prion protein PrP-(23–98) was recently found to polymerize into amyloid-like and proteinase K-resistant spherical aggregates in the presence of NADPH plus copper ions, we tested to determine whether calreticulin (CRT) inhibits PrP-(23–98) aggregation <I>in vitro</I>. …
NAID 10029592022

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リンク元	「カルレチキュリン」「カルレティキュリン」

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Calreticulin
	PDB rendering based on 1hhn.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2CLR, 3DOW, 3POS, 3POW
Identifiers
Symbols	CALR ; CRT; HEL-S-99n; RO; SSA; cC1qR
External IDs	OMIM: 109091 MGI: 88252 HomoloGene: 37911 GeneCards: CALR Gene
Gene ontology
Molecular function	• complement component C1q binding; • glycoprotein binding; • DNA binding; • mRNA binding; • integrin binding; • iron ion binding; • calcium ion binding; • protein binding; • zinc ion binding; • carbohydrate binding; • ubiquitin protein ligase binding; • peptide binding; • hormone binding; • protein binding involved in protein folding; • poly(A) RNA binding; • androgen receptor binding; • unfolded protein binding; • chaperone binding;
Cellular component	• acrosomal vesicle; • extracellular region; • proteinaceous extracellular matrix; • extracellular space; • intracellular; • nucleus; • cytoplasm; • endoplasmic reticulum; • endoplasmic reticulum lumen; • smooth endoplasmic reticulum; • Golgi apparatus; • cytosol; • polysome; • focal adhesion; • external side of plasma membrane; • cell surface; • membrane; • sarcoplasmic reticulum lumen; • MHC class I peptide loading complex; • perinuclear region of cytoplasm; • extracellular exosome; • integral component of lumenal side of endoplasmic reticulum membrane; • endocytic vesicle lumen;
Biological process	• negative regulation of transcription from RNA polymerase II promoter; • antigen processing and presentation of peptide antigen via MHC class I; • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; • peptide antigen assembly with MHC class I protein complex; • regulation of transcription, DNA-templated; • protein folding; • protein export from nucleus; • cellular calcium ion homeostasis; • receptor-mediated endocytosis; • cell cycle arrest; • spermatogenesis; • positive regulation of cell proliferation; • positive regulation of gene expression; • negative regulation of translation; • protein N-linked glycosylation via asparagine; • protein maturation by protein folding; • cortical actin cytoskeleton organization; • endoplasmic reticulum unfolded protein response; • response to estradiol; • negative regulation of intracellular steroid hormone receptor signaling pathway; • response to testosterone; • protein localization to nucleus; • protein folding in endoplasmic reticulum; • ATF6-mediated unfolded protein response; • regulation of meiotic nuclear division; • response to drug; • antigen processing and presentation of exogenous peptide antigen via MHC class I; • glucocorticoid receptor signaling pathway; • regulation of apoptotic process; • post-translational protein modification; • cellular protein metabolic process; • negative regulation of neuron differentiation; • positive regulation of DNA replication; • positive regulation of cell cycle; • negative regulation of transcription, DNA-templated; • negative regulation of retinoic acid receptor signaling pathway; • positive regulation of phagocytosis; • protein stabilization; • sequestering of calcium ion; • cardiac muscle cell differentiation; • chaperone-mediated protein folding; • cellular response to lithium ion; • cellular senescence; • positive regulation of substrate adhesion-dependent cell spreading; • positive regulation of dendritic cell chemotaxis;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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英: calreticulin
関: カルレティキュリン

「カルレティキュリン」

　　[★]

英: calreticulin
関: カルレチキュリン

[pmid2365822-1] McCauliffe DP, Zappi E, Lieu TS, Michalak M, Sontheimer RD, Capra JD (Jul 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"". The Journal of Clinical Investigation 86 (1): 332–5. doi:10.1172/JCI114704. PMC 296725. PMID 2365822.

[entrez-2] "Entrez Gene: calreticulin".

[3] Mobilferrin at the US National Library of Medicine Medical Subject Headings (MeSH)

[4] Beutler E, West C, Gelbart T (Jun 1997). "HLA-H and associated proteins in patients with hemochromatosis". Molecular Medicine (Cambridge, Mass.) 3 (6): 397–402. PMC 2230203. PMID 9234244.

[pmid12445456-5] Michalak M, Lynch J, Groenendyk J, Guo L, Robert Parker JM, Opas M (Nov 2002). "Calreticulin in cardiac development and pathology". Biochimica Et Biophysica Acta 1600 (1-2): 32–7. doi:10.1016/S1570-9639(02)00441-7. PMID 12445456.

[6] Murphy K (2011). Janeway's Immunobiology (8th ed.). Oxford: Taylor & Francis. ISBN 978-0815342434.

[7] "Entrez Gene: CALR calreticulin".

[pmid24325359-8] 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 (Dec 2013). "Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2". The New England Journal of Medicine 369 (25): 2391–405. doi:10.1056/NEJMoa1312542. PMC 3966280. PMID 24325359.

[pmid24325356-9] 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 (Dec 2013). "Somatic mutations of calreticulin in myeloproliferative neoplasms". The New England Journal of Medicine 369 (25): 2379–90. doi:10.1056/NEJMoa1311347. PMID 24325356.

[pmid21178137-10] 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 (Dec 2010). "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47". Science Translational Medicine 2 (63): 63ra94. doi:10.1126/scitranslmed.3001375. PMC 4126904. PMID 21178137. Lay summary – Stanford School of Medicine.

[pmid9671507-11] Andrin C, Pinkoski MJ, Burns K, Atkinson EA, Krahenbuhl O, Hudig D, Fraser SA, Winkler U, Tschopp J, Opas M, Bleackley RC, Michalak M (Jul 1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry 37 (29): 10386–94. doi:10.1021/bi980595z. PMID 9671507.

[pmid9988700-12] Perrone L, Tell G, Di Lauro R (Feb 1999). "Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain". The Journal of Biological Chemistry 274 (8): 4640–5. doi:10.1074/jbc.274.8.4640. PMID 9988700.

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calreticulin