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CALR (calreticulin)

Written2016-08João Agostinho Machado-Neto, Paula de Melo Campos, Fabiola Traina
Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo (JAMN, FT) Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, (PdMC), Brazil

Abstract Calreticulin (CALR) is a multifunctional protein involved in molecular chaperoning and calcium homeostasis. CALR has also been associated with proliferation, cell cycle progression, migration, invasion and anoikis resistance in cancer cells. The prognostic impact of CALR expression is yet to be elucidated, however in some types of cancer, high CALR expression has been related to worse clinical outcomes. Notably, the discovery of recurrent mutations in the exon 9 of the CALR gene in myeloproliferative neoplasms has opened a new round of investigations. The present review contains data on CALR DNA/RNA, protein encoded and function.

Keywords CALR; chromosome 19; calcium homeostasis; chaperone; cancer

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Identity

Alias_symbol (synonym)RO
SSA
cC1qR
CRT
FLJ26680
Other aliasHEL-S-99n
HGNC (Hugo) CALR
LocusID (NCBI) 811
Atlas_Id 904
Location 19p13.13  [Link to chromosome band 19p13]
Location_base_pair Starts at 12938600 and ends at 12944490 bp from pter ( according to hg19-Feb_2009)  [Mapping CALR.png]

DNA/RNA

Description The entire CALR gene is approximately 5.9 Kb (start: 12938578 and end: 12944489 bp; orientation: Plus strand) and contains 9 exons. The CALR cDNA contains 1.9 Kb.

Protein

 
  Figure 1. Schematic primary structure of CALR protein. The conserved P-domain, N-domain and C-domain and KDEL motif are illustrated. Amino acid (aa) positions are indicated.
Description CALR protein consists of 417 aminoacids with a molecular weight of 46 kDa and has a conserved P-domain, N-domain and C-domain. A KDEL (lysine, aspartic acid, glutamic acid and leucine) motif, which prevent secretion from endoplasmic reticulum, this protein is found in the C-terminal region. The representation of the primary structure of CALR protein is illustrated in Figure 1.
Expression Ubiquitous.
Localisation CALR is predominantly found in the cytoplasm and endoplasmic reticulum. Nuclear, membrane and cell surface localization has also been frequently reported.
Function CALR is a multifunctional protein, and molecular chaperoning and calcium homeostasis are the two most well-characterized functions of this protein. In the endoplasmatic reticulum, CALR binds to calcium, participates on folding of newly synthesized proteins and glycoproteins, and interacts with other chaperones as CANX (calnexin) (Gelebart, et al. 2005; Lu, et al. 2015; Zamanian, et al. 2013). Recently, evidence of the CALR participation in cell signaling networks has grown. CALR has been pointed out as a regulator of STAT3, STAT5, AKT, MAPK and PTK2 (FAK) cell signaling, promoting proliferation, cell cycle progression, migration, invasion and anoikis resistance (Chiang, et al. 2013; Du, et al. 2009; Feng, et al. 2015; Shi, et al. 2014; Wang, et al. 2013). CALR has also been described as a VEGFA and HIF1A inductor (Chen, et al. 2009; Weng, et al. 2015). Under stress conditions, CALR translocates onto the plasma membrane surface as a result of the CALR transport from endoplasmic reticulum to the Golgi apparatus, followed by exocytosis of CALR-containing vesicles, which acts as an "eat-me" signal (Zitvogel, et al. 2010). This process has been associated with immunogenic cell death (Apetoh, et al. 2007; Obeid, et al. 2007). In myeloproliferative neoplasms, mutated-CALR (exon 9 indel mutations) has been related to activation of MPL and JAK2 /STAT signaling, leading to cell proliferation and survival (Araki, et al. 2016; Balligand, et al. 2016; Chachoua, et al. 2016; Elf, et al. 2016; Marty, et al. 2016; Nivarthi, et al. 2016). A potential model for CALR network is summarized in Figure 2.
 
  Figure 2. A potential model for CALR network signaling. (Left panel) CALR binds to calcium, participates in the folding of newly synthesized glycoproteins, and interacts with other chaperones in the endoplasmatic reticulum. CALR regulates STAT3, STAT5, AKT, MAPK and FAK cell signaling, promoting proliferation, cell cycle progression, migration, invasion and anoikis resistance. Under stress condition, CALR translocates onto the plasma membrane by Golgi apparatus-mediated exocytosis, which participates in immunogenic cell death. (Right panel) Mutated-CALR (exon 9 indel mutations) induces activation of MPL and JAK2/STAT signaling, promoting cell proliferation and survival in myeloproliferative neoplasm cells. Abbreviations: ER, endoplasmic reticulum; Ca2+, calcium; MUT, mutated; P, phosphorylation. The Figure was produced using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).
Homology CALR belongs to the calreticulin family, which is comprised of endoplasmic reticulum calcium-binding chaperones. CALR shares high homology among different species (Table 1).

Table 1. Comparative identity of human CALR and other species



% Identity for: Homo sapiens CALR

Symbol

Protein

DNA

vs. P. troglodytes

CALR

100

99.9

vs. M. mulatta

CALR

99.8

97.6

vs. C. lupus

CALR

96.6

90.6

vs. B. taurus

CALR

94.8

89.6

vs. M. musculus

Calr

95.7

88.2

vs. R. norvegicus

Calr

95.7

87.7

vs. G. gallus

CALR3

65.4

66.4

vs. X. tropicalis

calr

83.1

76.6

vs. D. rerio

Calrl2

80.0

73.7

vs. D. melanogaster

Crc

72.4

69.9

vs. A. gambiae

AgaP_AGAP004212

71.5

69.3

vs. C. elegans

crt-1

67.1

67.4

vs. A. thaliana

CRT1a

56.0

61.6

vs. A. thaliana

CRT1b

57.1

59.6

vs. O. sativa

Os03g0832200

56.5

62.9

vs. O. sativa

Os07g0246200

59.1

62.8


(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic Mutations in exon 9 of the CALR gene have been described in 56 to 88% of non-mutated JAK2 and MPL myeloproliferative neoplasm (essential thrombocythemia and primary myelofibrosis) patients (Klampfl, et al. 2013; Nangalia, et al. 2013). Excluding myeloproliferative neoplasms, recurrent mutations in the CALR gene are rare. A total of 53 substitution missense, 7 substitution nonsense, 22 substitution synonymous, 798 insertion frameshift, 7 deletions inframe, 1493 deletion frameshift, 50 complex and 553 other mutations are reported in COSMIC, being 2939 mutations in hematopoietic and lymphoid cancers (Catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).

Implicated in

  
Entity Myeloproliferative neoplasms
Note In December 2013, two independent groups identified somatic mutations in the CALR gene in essential thrombocythemia and primary myelofibrosis patients with non-mutated JAK2 and MPL (Klampfl, et al. 2013; Nangalia, et al. 2013). CALR was also identified in a subset of patients with refractory anemia with ringed sideroblasts associated with marked thrombocytosis, but not in other hematological malignancies (Klampfl, et al. 2013). These finding were confirmed by several research groups (Grinsztejn, et al. 2016; Haslam, et al. 2016; Labastida-Mercado, et al. 2015; Li, et al. 2015; Lin, et al. 2015; Machado-Neto, et al. 2015; Monte-Mor, et al. 2016; Nunes, et al. 2015; Shirane, et al. 2015; Wojtaszewska, et al. 2015; Wu, et al. 2014). Over fifty different CALR mutations in exon 9 have been described, however the most frequent mutations (approximately 80%) are classified as type-1 (L367fs*46, deletion of 52bp) and type-2 (K385fs*47, insertion of 5bp). Patients with CALR-mutated myeloproliferative neoplasms have a lower age of disease onset, lower hemoglobin and platelet counts, and a better overall survival than either JAK2-mutated or CALR/JAK2/MPL wild-type patients (Chen, et al. 2014; Li, et al. 2014; Tefferi, et al. 2014b). In essential thrombocythemia, Pietra and colleagues (Pietra, et al. 2016) observed that CALR type 1-like mutations were mainly associated with a myelofibrosis phenotype and a higher risk of fibrotic transformation, whereas CALR type 2-like mutations were associated with an essential thrombocythemia phenotype, lower risk of thrombosis and an indolent clinical course. However, in primary myelofibrosis patients, CALR type 1-like mutations presented a better prognosis than patients with CALR type 2-like or JAK2 mutations (Guglielmelli, et al. 2015; Tefferi, et al. 2014a). CALR mutations were also reported in some cases of familial myeloproliferative neoplasms, but are rare in childhood essential thrombocythemia (Langabeer, et al. 2014; Lundberg, et al. 2014; Maffioli, et al. 2014). Gene expression signature studies on myeloproliferative neoplasm pathogenesis indicate a central role of the JAK/STAT signaling pathway in both JAK2 and CALR mutations, (Rampal, et al. 2014). Using a large panel of cancer cell lines, Kollmann and colleagues (Kollmann, et al. 2015) identified MARIMO as a leukemia cell line presenting a CALR mutation (61-bp deletion; c.1099_1159del; L367fs*43); surprisingly, this cell line showed neither JAK/STAT activation nor response to the treatment with the JAK1/2 inhibitor ruxolitinib.
  
  
Entity Acute myeloid leukemia
Note Balkhi and colleagues (Balkhi, et al. 2006) observed that CALR is acetylated in acute myeloid leukemia with t(8;21)(q22;q22). Previous studies also suggested that high CALR expression may be involved in repression of CEBPA in leukemia cells with inv(16) (p13q22) or t(8;21) (Helbling, et al. 2004; Helbling, et al. 2005). High CALR expression was observed in a subset of AML patients that are positive for XBP1s, a marker of unfolded protein response (Schardt, et al. 2009). Chemotherapy-independent CALR exposure at the cell surface was found in some acute myeloid leukemia patients, which was associated with low CD47 expression and enhanced cellular immune response against tumor antigens (Wemeau, et al. 2010). In samples from acute myeloid leukemia patients, CALR expression was increased in relation to samples from benign conditions, acute lymphoblastic leukemia and myeloproliferative neoplasms, however no association was observed with clinical and laboratorial characteristics (Park, et al. 2015).
  
  
Entity Chronic lymphocytic leukemia
Note CALR is highly expressed by stromal cells, which participate in the protective effect that stroma exerts on chronic lymphocytic leukemia cells by B-cell antigen receptor stimulation (Binder, et al. 2010). Molica and colleagues (Molica, et al. 2016) reported similar concentrations of CALR in serum from chronic lymphocytic leukemia and from healthy donors. However, elevated serum CALR was associated with higher peripheral blood lymphocytosis, Rai sub stages I-II and shorter treatment-free survival.
  
  
Entity Lymphoma
Note Vasostatin, a fragment of CALR (amino acids 1-180), was found to inhibit tumor formation capacity of the Burkitt lymphoma -cell line CA46 (Pike, et al. 1998). Similar results were found using a CALR fragment of amino acids 1-120 or 120-180 that also inhibits endothelial cell proliferation in vitro and Burkitt tumor growth (Pike, et al. 1999).
  
  
Entity Breast cancer
Note Using two-dimensional gel electrophoresis, Franzen and colleagues (Franzen, et al. 1997; Franzen, et al. 1996) observed an increase of CALR expression in high proliferative lesions from breast carcinoma compared to fibroadenoma (benign tumor) cells. Similar findings were reported by other research groups (Bini, et al. 1997; Chahed, et al. 2005; Kabbage, et al. 2013; Song, et al. 2012; Zamanian, et al. 2016) that also observed high CALR expression in breast cancer samples compared to histologically normal tissues using proteomics analysis. CALR overexpression was also correlated with lymph node metastasis and with postoperative appearance of distant metastases in ERBB2 (Her2/neu) positive breast cancer (Eric, et al. 2009). A multivariate analysis indicated that CALR expression is an independent predictor of tumor size and the occurrence of distant metastasis in a cohort of 228 breast cancer patients (Lwin, et al. 2010). Abundant CALR protein was found in breast tumor interstitial fluid compared to normal breast interstitial fluid (Gromov, et al. 2010). Serum levels of IgA of anti-calreticulin antibodies were higher in breast cancer patients compared to healthy donors (Eric-Nikolic, et al. 2012). mRNA and protein CALR expression was found to be expressed at higher levels in the breast cancer MDA-MB-231 cell line (more aggressive model) compared to breast cancer MCF7 cell line (less aggressive model) (Lwin, et al. 2010). CALR-silenced MCF-7 cells presented lower migration and invasion, and global gene expression profiling indicated a participation of TP53 and MAPK signaling pathways in these processes (Zamanian, et al. 2016).
  
  
Entity Ovarian cancer
Note Increased CALR expression, at the mRNA and protein levels, was observed in samples from ovarian cancer patients compared to samples from normal ovaries, benign tumors, and borderline tumors (Vera, et al. 2012). In ovarian cancer HOSE and A2780 cell lines, NGF (nerve growth factor) treatment resulted in induction of CALR expression, which was abolished by GW441756 treatment, a tropomyosin receptor kinase A selective inhibitor (Vera, et al. 2012). Overexpression of CALR was observed in solid metastases in comparison to effusions and primary ovarian carcinomas. High CALR expression in ovarian carcinoma effusions was associated with a better response to chemotherapy at diagnosis (Vaksman, et al. 2013).
  
  
Entity Prostate cancer
Note n prostate cancer cell lines, CALR is a hormone responsive gene and CALR inhibition, by antisense oligonucleotide, increases the sensitivity to calcimycin (A23187)-induced apoptosis (Zhu, et al. 1999). Using two-dimensional gel, a high expression of CALR was found in prostate carcinoma compared to prostate hyperplasia (Alaiya, et al. 2000). On the other hand, Alur and colleagues (Alur, et al. 2009) observed that CALR is downregulated in cancer cells compared to adjacent benign glandular epithelial cells using immunohistochemical analysis. In the prostate cancer LNCaP cell line, induction of neuroendocrine differentiation reduces CALR expression and modulates intracellular Ca2+ homeostasis (Vanoverberghe, et al. 2004). In contrast, CALR was downregulated in poorly-differentiated tumors, though not in well-differentiated tumors in a murine prostate cancer model (Ruddat, et al. 2005). Increased CALR expression was observed in 1E8-H cells (prostate cancer cell line with high metastatic potential) compared to 2B4-L (prostate cancer cell line with low metastatic potential) (Wu, et al. 2007). In the human prostate cancer PC3 cell line, induction of CALR expression resulted in lower clonogenic capacity and xenograft tumor growth (Alur, et al. 2009). In rat Dunning AT3.1 prostate cancer cell line, induction of CALR overexpression did not modulate tumor growth, but reduced lung macrometastasis (Alur, et al. 2009). Docetaxel-resistant PC3 cells presented high levels of CALR compared to docetaxel-sensitive PC3 cells (Zu, et al. 2015).
  
  
Entity Bladder cancer
Note Using proteomic analysis, Kageyama and colleagues (Kageyama, et al. 2004) reported an increased expression of CALR in bladder cancer compared to normal urothelium, and suggested that CALR may be a biomarker for bladder cancer with a sensitivity of 73% and a specificity of 86%. Latterly, the same research group led by Yoshiki (Iwaki, et al. 2004) validated these findings in a larger cohort of bladder cancer patients and controls (112 and 230, respectively), and CALR expression combined with other markers ( SNCG (synuclein gamma) and COMT (catechol-o-methyltransferase)) displayed a sensitivity of 76.8% and a specificity of 77.4% as bladder cancer biomarkers (CALR alone presented a sensitivity of 71.4% and a specificity of 77.8%). Yoshiki's group (Kageyama, et al. 2009) also reported that CALR was highly expressed in urine samples from bladder urothelial carcinoma patients compared to urological patients without urothelial carcinoma and non-urological patients, and suggested that urinary CALR concentration may be a useful biomarker for bladder urothelial carcinoma with a sensitivity of 67.9% and specificity of 80.0%. In another study, urinary CALR was indicated as a potential biomarker for urothelial urinary bladder carcinoma (Soukup, et al. 2015). In the human bladder cancer J82 cell line, CALR silencing reduced cell viability, cell cycle progression, adhesion, migration, PXN (Paxillin)/FAK axis activation, FUT1 expression and in vivo tumor growth and metastasis (Lu, et al. 2014b; Lu, et al. 2011).
CALR expression was increased in urine from urothelial transitional cell carcinoma compared to healthy donors (Lu, et al. 2014a).
  
  
Entity Oral squamous cell carcinoma
Note High prevalence of CALR expression positivity was observed in oral squamous cell carcinoma samples (96%) compared to non-cancerous matched tissue (32%). Similarly, oral squamous cell carcinoma cell lines (Ca9-22,CAL-27, HSC-3, SCC-9, SAS and FaDu) presented higher CALR expression than human oral keratinocytes (Chiang, et al. 2013). In SAS cells, CALR knockdown reduced cell proliferation, clonogenicity, anchorage-independent growth, migration, and Paxillin/FAK and MAPK activation (Chiang, et al. 2013).
  
  
Entity Esophageal squamous cell carcinoma
Note CALR upregulation was observed in esophageal squamous cell carcinoma compared to adjacent nonmalignant tissue by two dimensional electrophoresis and mass spectrometry analysis (Jazii, et al. 2006; Nishimori, et al. 2006). In agreement, Du and colleagues (Du, et al. 2007) observed an increased CALR expression in esophageal squamous cell carcinoma samples compared to matched adjacent normal tissue, using two dimensional electrophoresis, western blot and/or immunohistochemistry, which was associated with a poorer prognosis by univariate analysis. Latterly, Du and colleagues (Du, et al. 2009), in an elegant mechanistic study, demonstrated that CALR inhibition reduced cell migration and invasion, clonogenic potential and in vivo tumor growth, and induced anoikis in esophageal squamous cell carcinoma cell lines. In the esophageal squamous cell carcinoma KYSE450 cells, CALR silencing reduces CTTN expression, and AKT and STAT3 activation (Du, et al. 2009). The same research group showed that CALR regulates PTPN1 (PTP1B) and NRP1 expression, at mRNA and protein levels, and STAT5 and ERK activation (Shi, et al. 2014; Wang, et al. 2013).
  
  
Entity Gastric cancer
Note High CALR expression was observed in 20 out of 30 gastric cancer patients comparing matched tumor and non-tumor specimens (Chen, et al. 2009) using cDNA microarray (discovery cohort). Similar results were observed in an independent cohort of validation (enrolling 79 gastric cancer patients), in which high CALR expression was associated with high microvessel density, positive serosal invasion, lymph node metastasis, perineural invasion and poor survival (by multivariate analysis) (Chen, et al. 2009). Functional analysis using AGS human gastric cancer cell line denoted that CALR overexpression resulted in increased proliferation, cell cycle progression, migration and PIGF and VEGF secretion, whereas CALR inhibition resulted in the opposite effect (Chen, et al. 2009).
  
  
Entity Colorectal adenocarcinoma
Note Using high-resolution two-dimensional gel analysis, CALR was found to be an abundant protein in the nuclear matrix of colon cancer cells, though not of normal colon tissue (Brunagel, et al. 2003). Low CALR expression was observed in colon cancer compared to normal colon tissue (Alfonso, et al. 2005; Toquet, et al. 2007). Similarly, Peng and colleagues (Peng, et al. 2010) observed reduced expression of CALR in colon tumors in relation to adjacent normal epithelium; of note, CALR expression was associated with T-cell infiltration and better survival rates in colon cancer patients by univariate analysis. CALR downregulation was also observed in colonic cancer cell lines (SW1116, SW620, SW480, HT29, HT29-Cl.19A, HT29-Cl.16E and Colo320 cells) compared to primary normal colonic epithelial cells (Toquet, et al. 2007). In contrast, Vougas and colleagues (Vougas, et al. 2008) reported high CALR expression in colon cancer compared to the matched mirror biopsy tissues, especially in highly malignant and poorly differentiated tumors.
In sera, anti-calreticulin antibodies were found in 57% of colorectal adenocarcinoma patients and in 2% of healthy donors (Pekarikova, et al. 2010). High MIR27A -expressing cells displayed less CALR on the cell surface (Colangelo, et al. 2016b), which impaired the kinetics of apoptosis in drug-induced immunogenic cell death of human colorectal cancer HCT116 cells (Colangelo, et al. 2016a).
  
  
Entity Hepatocellular carcinoma
Note Yoon and colleagues (Yoon, et al. 2000) researching for nuclear matrix proteins differently expressed in hepatocellular carcinoma found CALR to be present in the nuclear matrix fraction of carcinomas, though not in the nonmalignant liver tissue. Increased CALR expression was also reported in the human hepatoma cell line BEL-7404 compared to normal human liver cell line L-02 (Yu, et al. 2000). The investigation of differentially expressed proteins in high (MHCC97-H) and low (MHCC97-L) metastatic hepatocellular carcinoma cell lines found that CALR is downregulated in high metastatic hepatocellular carcinoma MHCC97-H cell line compared to MHCC97-L cells (Ding, et al. 2004). CALR protein fragments were detected at higher levels in the serum from hepatocellular carcinoma patients in relation to the serum from healthy individuals, from chronic hepatitis patients, or from cirrhosis patients, suggesting that serum CALR fragments may be biomarkers for hepatocellular carcinoma (Chignard, et al. 2006). Serum anti-calreticulin antibodies have been found in 63% of hepatocellular carcinoma patients, suggesting that CALR is a molecular target for B cell molecular in this malignancy (Pekarikova, et al. 2010). In the hepatocellular carcinoma SMMC7721 and HepG2 cell lines, CALR silencing reduced cell viability, cell cycle progression, invasion and AKT activation (Feng, et al. 2015).
  
  
Entity Pancreatic adenocarcinoma
Note Anti-calreticulin antibodies were found in 47% of sera from pancreatic adenocarcinoma patients compared to 2% from healthy donors (Pekarikova, et al. 2010). Higher CALR expression was found in pancreatic tumors in comparison to paired non-cancerous pancreatic ductal tissues, and was associated with more advanced lymph node metastasis, high grade stage and worse overall survival (by univariate analysis) (Sheng, et al. 2014). In pancreatic cancer cell lines, CALR silencing reduced proliferation, migration, ERK activation, and did not modulate TP53, MDM2 , phospho-AKT, phospho-JUNK and phospho-p38 MAPK, wheras CALR overexpression increased migration and ERK activation, but did not modulate TP53, MDM2 and phospho-AKT expression (Sheng, et al. 2014).
Xenograft pancreatic tumors treated with adenovirus expressing vasostatin presented lower tumor size and reduced angiogenesis compared to those treated with a control adenovirus (Li, et al. 2006). On the other hand, vasostatin-expressing BON cells, a pancreatic carcinoid tumor cell line, showed enhanced cell proliferation, invasion and in vivo tumor formation (Liu, et al. 2005). Using two-dimensional gel electrophoresis, increased CALR expression was observed in pancreatic cancer samples compared to matched non-cancerous pancreatic samples (Wang, et al. 2012), and in serum from pancreatic cancer patients compared to serum from healthy donors (Hong, et al. 2004).
  
  
Entity Lung cancer
Note CARL protein levels were significantly higher in serum samples of lung cancer patients compared to healthy individuals. Immunohistochemistry analysis showed an increased CALR expression in lung cancer cells in comparison to normal lung cells, which was associated with tumor pathological grade (Liu, et al. 2012). In a large cohort of lung cancers (270 patients), CALR expression was heterogeneous, found in cytoplasm and at the surface of tumor cells and was not associated with tumor stage (Fucikova, et al. 2016). High CALR expression was associated with tumor infiltration by immune cells and low CALR expression impacted negatively on overall survival by univariate and multivariate analysis (Fucikova, et al. 2016). Pemetrexed-resistant A549 adenocarcinomic human alveolar basal epithelial cells presented elevated levels of CALR compared to pemetrexed-sensitive A549 cells. CALR silencing rescued, at least in part, sensibility to pemetrexed treatment in pemetrexed-resistant A549 cells, whereas induction of increased CALR expression reduced sensibility to pemetrexed treatment of pemetrexed-sensitive A549 cells (Chou, et al. 2015).
  
  
Entity Glioblastoma
Note Okunaga and colleagues (Okunaga, et al. 2006) reported that the neuroglioma H4 cell line (radiosensitive cells) expressed high levels of CALR compared to the glioblastoma cell lines U251MG and T98G (radioresistant cells). The authors also observed that the induction of CALR expression by transfection enhanced radiation-produced apoptosis in U251MG cells (Okunaga, et al. 2006). In glioma patients, CALR expression was reduced compared to normal brain tissue, and negative CALR expression was associated with higher grade disease and reduced overall survival by univariate analysis (Gao, et al. 2013). CALR expression was increased in 5 out of 9 relapsed glioblastoma patients that presented low levels of CALR expression(Muth, et al. 2016).
  
  
Entity Neuroblastoma
Note Using immunohistochemical, Hsu and colleagues (Hsu, et al. 2005) observed that 47% of neuroblastoma samples were positive for CALR expression, which associated with age at diagnosis ≤1 year, early clinical stage, differentiated tumors and non-amplified MYCN. The authors also showed that positive CALR expression was an independent factor for better overall survival by multivariable analysis (Hsu, et al. 2005). In neuroblastoma cell lines (SH-SY5Y, SK-N-DZ and stNB-V1), CALR inhibition resulted in VEGFA and HIF1A downregulation, whereas CALR overexpression led to increased levels of VEGFA and HIF1A (Weng, et al. 2015).
  
  
Entity Melanoma
Note Increased CALR expression was found upon ionizing radiation and associated with radio resistance of the melanoma cell line SQ-20B (Ramsamooj, et al. 1995). In melanoma samples, a similar profile of CALR expression was observed between primary tumors and metastatic lesions (Dissemond, et al. 2004). Using a proteomic approach, a higher CALR expression was observed in the melanoma 526 cell line compared to melanocytes (FOM78) (Caputo, et al. 2011).
  
  
Entity Liposarcoma
Note CALR was expressed in both dedifferentiated areas and atypical stromal cells and/or lipoblasts in the well-differentiated areas in liposarcomas, thought not in normal fat tissue (Hisaoka, et al. 2012). The authors associated CALR upregulation with the downregulation of MIR1275 , a putative microRNA that targets CALR. In addition, CALR silencing reduces cell proliferation and induces adipogenesis in the dedifferentiated liposarcoma FU-DDLS-1 cell line (Hisaoka, et al. 2012).
  
  
Entity Fibrosarcoma
Note Using fibrosarcoma murine cell line models that present regressive (QR-32 cells) and progressive (QRsP-11 cells) tumor formation in mice, Hayashi and colleagues reported that QRsP-11 cells presented higher expression of CALR compared to QR-32 cells (Hayashi, et al. 2005).
  
  
Entity Thyroid cancer
Note Thyroid cell lines transformed by mutant TP53 presented CALR downregulation (Paron, et al. 2005). CALR expression was found to be lower in malignant follicular thyroid carcinoma compared with benign follicular thyroid adenoma using proteomics analysis validated by immunohistochemistry (Netea-Maier, et al. 2008).
  
  
Entity Adrenocortical carcinomas
Note Elevated CALR expression was identified in adrenocortical carcinomas compared to adjacent normal adrenocortical tissues, which was associated with higher grade tumors (Yang, et al. 2013).
  
  
Entity Pituitary adenoma
Note Desiderio and Zhan (Desiderio, et al. 2003), using proteomics approaches, found CALR to be a differently expressed protein in pituitary adenoma compared to control tissue.
  

To be noted

The discovery of the recurrent exon 9 indel CALR mutations in myeloproliferative neoplasms combined with the fact that these mutations are mutually exclusive with JAK2 and MPL mutations (except in very rare cases) was a marked advance in the elucidation of the molecular basis of these neoplasms. Recently, studies using cellular and animal models have provided important information regarding the mechanisms of action of the mutated-CALR protein. Results from several independent research groups converge to the same point: mutated CALR activates the thrombopoietin receptor (MPL) and leads to the activation of MPL downstream targets, including JAK2/STAT and MAPK signaling pathways. Furthermore, MPL inhibition in cellular models (MPL-expressing Ba/F3 or UT-7 cell lines) and MPL knockout in mice prevent the transformation caused by the CALR mutation, providing new therapeutic possibilities for myeloproliferative neoplasm patients (Araki, et al. 2016; Balligand, et al. 2016; Chachoua, et al. 2016; Elf, et al. 2016; Marty, et al. 2016; Nivarthi, et al. 2016). Other notable cancer-related findings are that aberrant CALR exposure at cell surface caused by reticulum stress in hyperploid cancer cells represents an important mechanism to avoid cancer development and progression by immunosurveillance (Senovilla, et al. 2012).

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Brünagel G, Shah U, Schoen RE, Getzenberg RH
J Cell Biochem 2003 May 15;89(2):238-43
PMID 12704787
 
Characterization of human melanoma cell lines and melanocytes by proteome analysis
Caputo E, Maiorana L, Vasta V, Pezzino FM, Sunkara S, Wynne K, Elia G, Marincola FM, McCubrey JA, Libra M, Travali S, Kane M
Cell Cycle 2011 Sep 1;10(17):2924-36
PMID 21857157
 
Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants
Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu RI, Marty C, Gryshkova V, Defour JP, Vertenoeil G, Ngo A, Koay A, Raslova H, Courtoy PJ, Choong ML, Plo I, Vainchenker W, Kralovics R, Constantinescu SN
Blood 2016 Mar 10;127(10):1325-35
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Expression of fibrinogen E-fragment and fibrin E-fragment is inhibited in the human infiltrating ductal carcinoma of the breast: the two-dimensional electrophoresis and MALDI-TOF-mass spectrometry analyses
Chahed K, Kabbage M, Ehret-Sabatier L, Lemaitre-Guillier C, Remadi S, Hoebeke J, Chouchane L
Int J Oncol 2005 Nov;27(5):1425-31
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Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia
Chen CC, Gau JP, Chou HJ, You JY, Huang CE, Chen YY, Lung J, Chou YS, Leu YW, Lu CH, Lee KD, Tsai YH
Ann Hematol 2014 Dec;93(12):2029-36
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Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer
Chen CN, Chang CC, Su TE, Hsu WM, Jeng YM, Ho MC, Hsieh FJ, Lee PH, Kuo ML, Lee H, Chang KJ
Ann Surg Oncol 2009 Feb;16(2):524-33
PMID 19050968
 
Calreticulin, an endoplasmic reticulum-resident protein, is highly expressed and essential for cell proliferation and migration in oral squamous cell carcinoma
Chiang WF, Hwang TZ, Hour TC, Wang LH, Chiu CC, Chen HR, Wu YJ, Wang CC, Wang LF, Chien CY, Chen JH, Hsu CT, Chen JY
Oral Oncol 2013 Jun;49(6):534-41
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Cleavage of endoplasmic reticulum proteins in hepatocellular carcinoma: Detection of generated fragments in patient sera
Chignard N, Shang S, Wang H, Marrero J, Bréchot C, Hanash S, Beretta L
Gastroenterology 2006 Jun;130(7):2010-22
PMID 16762624
 
Identification of Up- and Down-Regulated Proteins in Pemetrexed-Resistant Human Lung Adenocarcinoma: Flavin Reductase and Calreticulin Play Key Roles in the Development of Pemetrexed-Associated Resistance
Chou HC, Chen JY, Lin DY, Wen YF, Lin CC, Lin SH, Lin CH, Chung TW, Liao EC, Chen YJ, Wei YS, Tsai YT, Chan HL
J Proteome Res 2015 Nov 6;14(11):4907-20
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The miR-27a-calreticulin axis affects drug-induced immunogenic cell death in human colorectal cancer cells
Colangelo T, Polcaro G, Ziccardi P, Muccillo L, Galgani M, Pucci B, Milone MR, Budillon A, Santopaolo M, Mazzoccoli G, Matarese G, Sabatino L, Colantuoni V
Cell Death Dis 2016 Feb 25;7:e2108
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The human pituitary proteome: the characterization of differentially expressed proteins in an adenoma compared to a control
Desiderio DM, Zhan X
Cell Mol Biol (Noisy-le-grand) 2003 Jul;49(5):689-712
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Proteome analysis of hepatocellular carcinoma cell strains, MHCC97-H and MHCC97-L, with different metastasis potentials
Ding SJ, Li Y, Shao XX, Zhou H, Zeng R, Tang ZY, Xia QC
Proteomics 2004 Apr;4(4):982-94
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Differential downregulation of endoplasmic reticulum-residing chaperones calnexin and calreticulin in human metastatic melanoma
Dissemond J, Busch M, Kothen T, Mörs J, Weimann TK, Lindeke A, Goos M, Wagner SN
Cancer Lett 2004 Jan 20;203(2):225-31
PMID 14732231
 
Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma
Du XL, Hu H, Lin DC, Xia SH, Shen XM, Zhang Y, Luo ML, Feng YB, Cai Y, Xu X, Han YL, Zhan QM, Wang MR
J Mol Med (Berl) 2007 Aug;85(8):863-75
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Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma
Du XL, Yang H, Liu SG, Luo ML, Hao JJ, Zhang Y, Lin DC, Xu X, Cai Y, Zhan QM, Wang MR
Oncogene 2009 Oct 22;28(42):3714-22
PMID 19684620
 
Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation
Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman JA, Schneider RK, Al-Shahrour F, Mullally A
Cancer Discov 2016 Apr;6(4):368-81
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Effects of humoral immunity and calreticulin overexpression on postoperative course in breast cancer
Erić A, Juranić Z, Milovanović Z, Marković I, Inić M, Stanojević-Bakić N, Vojinović-Golubović V
Pathol Oncol Res 2009 Mar;15(1):89-90
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Calreticulin down-regulation inhibits the cell growth, invasion and cell cycle progression of human hepatocellular carcinoma cells
Feng R, Ye J, Zhou C, Qi L, Fu Z, Yan B, Liang Z, Li R, Zhai W
Diagn Pathol 2015 Aug 27;10:149
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Analysis of polypeptide expression in benign and malignant human breast lesions: down-regulation of cytokeratins
Franzén B, Linder S, Alaiya AA, Eriksson E, Uruy K, Hirano T, Okuzawa K, Auer G
Br J Cancer 1996 Nov;74(10):1632-8
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Calreticulin Expression in Human Non-Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis
Fucikova J, Becht E, Iribarren K, Goc J, Remark R, Damotte D, Alifano M, Devi P, Biton J, Germain C, Lupo A, Fridman WH, Dieu-Nosjean MC, Kroemer G, Sautès-Fridman C, Cremer I
Cancer Res 2016 Apr 1;76(7):1746-56
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Correlation of expression levels of ANXA2, PGAM1, and CALR with glioma grade and prognosis
Gao H, Yu B, Yan Y, Shen J, Zhao S, Zhu J, Qin W, Gao Y
J Neurosurg 2013 Apr;118(4):846-53
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Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum
Gelebart P, Opas M, Michalak M
Int J Biochem Cell Biol 2005 Feb;37(2):260-6
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The prevalence of CALR mutations in a cohort of patients with myeloproliferative neoplasms
Grinsztejn E, Percy MJ, McClenaghan D, Quintana M, Cuthbert RJ, McMullin MF
Int J Lab Hematol 2016 Feb;38(1):102-6
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Up-regulated proteins in the fluid bathing the tumour cell microenvironment as potential serological markers for early detection of cancer of the breast
Gromov P, Gromova I, Bunkenborg J, Cabezon T, Moreira JM, Timmermans-Wielenga V, Roepstorff P, Rank F, Celis JE
Mol Oncol 2010 Feb;4(1):65-89
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Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis
Guglielmelli P, Rotunno G, Fanelli T, Pacilli A, Brogi G, Calabresi L, Pancrazzi A, Vannucchi AM
Blood Cancer J 2015 Oct 16;5:e360
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CALR mutation profile in Irish patients with myeloproliferative neoplasms
Haslam K, Conneally E, Flynn CM, Cahill MR, Gilligan O, O'Shea D, Langabeer SE
Hematol Oncol Stem Cell Ther 2016 Sep;9(3):112-5
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Proteomic profiling for cancer progression: Differential display analysis for the expression of intracellular proteins between regressive and progressive cancer cell lines
Hayashi E, Kuramitsu Y, Okada F, Fujimoto M, Zhang X, Kobayashi M, Iizuka N, Ueyama Y, Nakamura K
Proteomics 2005 Mar;5(4):1024-32
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The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin
Helbling D, Mueller BU, Timchenko NA, Hagemeijer A, Jotterand M, Meyer-Monard S, Lister A, Rowley JD, Huegli B, Fey MF, Pabst T
Proc Natl Acad Sci U S A 2004 Sep 7;101(36):13312-7
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Aberrant calreticulin expression is involved in the dedifferentiation of dedifferentiated liposarcoma
Hisaoka M, Matsuyama A, Nakamoto M
Am J Pathol 2012 May;180(5):2076-83
PMID 22429966
 
An autoantibody-mediated immune response to calreticulin isoforms in pancreatic cancer
Hong SH, Misek DE, Wang H, Puravs E, Giordano TJ, Greenson JK, Brenner DE, Simeone DM, Logsdon CD, Hanash SM
Cancer Res 2004 Aug 1;64(15):5504-10
PMID 15289361
 
Calreticulin expression in neuroblastoma--a novel independent prognostic factor
Hsu WM, Hsieh FJ, Jeng YM, Kuo ML, Chen CN, Lai DM, Hsieh LJ, Wang BT, Tsao PN, Lee H, Lin MT, Lai HS, Chen WJ
Ann Oncol 2005 Feb;16(2):314-21
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Diagnostic potential in bladder cancer of a panel of tumor markers (calreticulin, gamma -synuclein, and catechol-o-methyltransferase) identified by proteomic analysis
Iwaki H, Kageyama S, Isono T, Wakabayashi Y, Okada Y, Yoshimura K, Terai A, Arai Y, Iwamura H, Kawakita M, Yoshiki T
Cancer Sci 2004 Dec;95(12):955-61
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Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer
Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH
World J Gastroenterol 2006 Nov 28;12(44):7104-12
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Calreticulin expression in infiltrating ductal breast carcinomas: relationships with disease progression and humoral immune responses
Kabbage M, Trimeche M, Bergaoui S, Hammann P, Kuhn L, Hamrita B, ben Nasr H, Chaieb A, Chouchane L, Chahed K
Tumour Biol 2013 Apr;34(2):1177-88
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Identification by proteomic analysis of calreticulin as a marker for bladder cancer and evaluation of the diagnostic accuracy of its detection in urine
Kageyama S, Isono T, Iwaki H, Wakabayashi Y, Okada Y, Kontani K, Yoshimura K, Terai A, Arai Y, Yoshiki T
Clin Chem 2004 May;50(5):857-66
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MARIMO cells harbor a CALR mutation but are not dependent on JAK2/STAT5 signaling
Kollmann K, Nangalia J, Warsch W, Quentmeier H, Bench A, Boyd E, Scott M, Drexler HG, Green AR
Leukemia 2015 Feb;29(2):494-7
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The mutation profile of JAK2, MPL and CALR in Mexican patients with Philadelphia chromosome-negative myeloproliferative neoplasms
Labastida-Mercado N, Galindo-Becerra S, Garcés-Eisele J, Colunga-Pedraza P, Guzman-Olvera V, Reyes-Nuñez V, Ruiz-Delgado GJ, Ruiz-Argüelles GJ
Hematol Oncol Stem Cell Ther 2015 Mar;8(1):16-21
PMID 25637689
 
CALR mutations are rare in childhood essential thrombocythemia
Langabeer SE, Haslam K, McMahon C
Pediatr Blood Cancer 2014 Aug;61(8):1523
PMID 24523226
 
Calreticulin mutations in Chinese with primary myelofibrosis
Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, Yang L, Xing R, Ai X, Qin T, Zhang Y, Zhang P, Xiao Z
Haematologica 2014 Nov;99(11):1697-700
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Treatment of pancreatic carcinoma by adenoviral mediated gene transfer of vasostatin in mice
Li L, Yuan YZ, Lu J, Xia L, Zhu Y, Zhang YP, Qiao MM
Gut 2006 Feb;55(2):259-65
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Frequency and allele burden of CALR mutations in Chinese with essential thrombocythemia and primary myelofibrosis without JAK2(V617F) or MPL mutations
Li N, Yao QM, Gale RP, Li JL, Li LD, Zhao XS, Jiang H, Jiang Q, Jiang B, Shi HX, Chen SS, Liu KY, Huang XJ, Ruan GR
Leuk Res 2015 May;39(5):510-4
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The Prevalence of JAK2, MPL, and CALR Mutations in Chinese Patients With BCR-ABL1-Negative Myeloproliferative Neoplasms
Lin Y, Liu E, Sun Q, Ma J, Li Q, Cao Z, Wang J, Jia Y, Zhang H, Song Z, Ai X, Shi L, Feng X, Li C, Wang J, Ru K
Am J Clin Pathol 2015 Jul;144(1):165-71
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Gene transfer of vasostatin, a calreticulin fragment, into neuroendocrine tumor cells results in enhanced malignant behavior
Liu M, Imam H, Oberg K, Zhou Y
Neuroendocrinology 2005;82(1):1-10
PMID 16293970
 
Calreticulin as a potential diagnostic biomarker for lung cancer
Liu R, Gong J, Chen J, Li Q, Song C, Zhang J, Li Y, Liu Z, Dong Y, Chen L, Jin B
Cancer Immunol Immunother 2012 Jun;61(6):855-64
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A panel of tumor markers, calreticulin, annexin A2, and annexin A3 in upper tract urothelial carcinoma identified by proteomic and immunological analysis
Lu CM, Lin JJ, Huang HH, Ko YC, Hsu JL, Chen JC, Din ZH, Wu YJ
BMC Cancer 2014 May 23;14:363
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Changes in tumor growth and metastatic capacities of J82 human bladder cancer cells suppressed by down-regulation of calreticulin expression
Lu YC, Chen CN, Wang B, Hsu WM, Chen ST, Chang KJ, Chang CC, Lee H
Am J Pathol 2011 Sep;179(3):1425-33
PMID 21723245
 
Functional roles of calreticulin in cancer biology
Lu YC, Weng WC, Lee H
Biomed Res Int 2015;2015:526524
PMID 25918716
 
Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms
Lundberg P, Nienhold R, Ambrosetti A, Cervantes F, Pérez-Encinas MM, Skoda RC
Blood 2014 Apr 24;123(17):2744-5
PMID 24764562
 
Clinicopathological significance of calreticulin in breast invasive ductal carcinoma
Lwin ZM, Guo C, Salim A, Yip GW, Chew FT, Nan J, Thike AA, Tan PH, Bay BH
Mod Pathol 2010 Dec;23(12):1559-66
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Somatic mutations of calreticulin in a Brazilian cohort of patients with myeloproliferative neoplasms
Machado-Neto JA, de Melo Campos P, de Albuquerque DM, Costa FF, Lorand-Metze I, Olalla Saad ST, Traina F
Rev Bras Hematol Hemoter 2015 May-Jun;37(3):211-4
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Looking for CALR mutations in familial myeloproliferative neoplasms
Maffioli M, Genoni A, Caramazza D, Mora B, Bussini A, Merli M, Giorgino T, Casalone R, Passamonti F
Leukemia 2014 Jun;28(6):1357-60
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Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis
Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, Villeval JL, Raslova H, Kralovics R, Constantinescu SN, Plo I, Vainchenker W
Blood 2016 Mar 10;127(10):1317-24
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Serum levels of soluble calreticulin predict for time to first treatment in early chronic lymphocytic leukaemia
Molica S, Digiesi G, D'Arena G, Mirabelli R, Antenucci A, Conti L, Gentile M, Musto P, Neri A, Morabito F
Br J Haematol 2016 Jan 5
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Clinical features of JAK2V617F- or CALR-mutated essential thrombocythemia and primary myelofibrosis
Monte-Mor Bda C, Ayres-Silva Jde P, Correia WD, Coelho AC, Solza C, Daumas AH, Bonamino MH, Santos FP, Datoguia TS, Pereira Wde O, Lisboa BC, Ramos CF, Machado-Neto JA, Hamerschlak N, Campregher PV, Traina F, Pagnano KB, Zalcberg I
Blood Cells Mol Dis 2016 Sep;60:74-7
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Primary glioblastoma multiforme tumors and recurrence : Comparative analysis of the danger signals HMGB1, HSP70, and calreticulin
Muth C, Rubner Y, Semrau S, Rühle PF, Frey B, Strnad A, Buslei R, Fietkau R, Gaipl US
Strahlenther Onkol 2016 Mar;192(3):146-55
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Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
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
N Engl J Med 2013 Dec 19;369(25):2391-405
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Discovery and validation of protein abundance differences between follicular thyroid neoplasms
Netea-Maier RT, Hunsucker SW, Hoevenaars BM, Helmke SM, Slootweg PJ, Hermus AR, Haugen BR, Duncan MW
Cancer Res 2008 Mar 1;68(5):1572-80
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Proteomic analysis of primary esophageal squamous cell carcinoma reveals downregulation of a cell adhesion protein, periplakin
Nishimori T, Tomonaga T, Matsushita K, Oh-Ishi M, Kodera Y, Maeda T, Nomura F, Matsubara H, Shimada H, Ochiai T
Proteomics 2006 Feb;6(3):1011-8
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Thrombopoietin receptor is required for the oncogenic function of CALR mutants
Nivarthi H, Chen D, Cleary C, Kubesova B, Jäger R, Bogner E, Marty C, Pecquet C, Vainchenker W, Constantinescu SN, Kralovics R
Leukemia 2016 Aug;30(8):1759-63
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CALR mutations screening in wild type JAK2(V617F) and MPL(W515K/L) Brazilian myeloproliferative neoplasm patients
Nunes DP, Lima LT, Chauffaille Mde L, Mitne-Neto M, Santos MT, Cliquet MG, Guerra-Shinohara EM
Blood Cells Mol Dis 2015 Oct;55(3):236-40
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Calreticulin exposure dictates the immunogenicity of cancer cell death
Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Métivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G
Nat Med 2007 Jan;13(1):54-61
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Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells
Okunaga T, Urata Y, Goto S, Matsuo T, Mizota S, Tsutsumi K, Nagata I, Kondo T, Ihara Y
Cancer Res 2006 Sep 1;66(17):8662-71
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Calreticulin mRNA expression and clinicopathological characteristics in acute myeloid leukemia
Park S, Huh HJ, Mun YC, Seong CM, Chung WS, Chung HS, Huh J
Cancer Genet 2015 Dec;208(12):630-5
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A differential proteomic approach to identify proteins associated with thyroid cell transformation
Paron I, D'Ambrosio C, Scaloni A, Berlingieri MT, Pallante PL, Fusco A, Bivi N, Tell G, Damante G
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Calreticulin is a B cell molecular target in some gastrointestinal malignancies
Pekáriková A, Sánchez D, Palová-Jelínková L, Simsová M, Benes Z, Hoffmanová I, Drastich P, Janatková I, Mothes T, Tlaskalová-Hogenová H, Tucková L
Clin Exp Immunol 2010 May;160(2):215-22
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Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer
Peng RQ, Chen YB, Ding Y, Zhang R, Zhang X, Yu XJ, Zhou ZW, Zeng YX, Zhang XS
World J Gastroenterol 2010 May 21;16(19):2428-34
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Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms
Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, Sant'Antonio E, Abbonante V, Moccia F, Casetti IC, Bellini M, Renna MC, Roncoroni E, Fugazza E, Astori C, Boveri E, Rosti V, Barosi G, Balduini A, Cazzola M
Leukemia 2016 Feb;30(2):431-8
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Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth
Pike SE, Yao L, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Teruya-Feldstein J, Wirth P, Gupta G, Tosato G
J Exp Med 1998 Dec 21;188(12):2349-56
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Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis
Rampal R, Al-Shahrour F, Abdel-Wahab O, Patel JP, Brunel JP, Mermel CH, Bass AJ, Pretz J, Ahn J, Hricik T, Kilpivaara O, Wadleigh M, Busque L, Gilliland DG, Golub TR, Ebert BL, Levine RL
Blood 2014 May 29;123(22):e123-33
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Enhanced expression of calreticulin in the nucleus of radioresistant squamous carcinoma cells in response to ionizing radiation
Ramsamooj P, Notario V, Dritschilo A
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Evidence for downregulation of calcium signaling proteins in advanced mouse adenocarcinoma
Ruddat VC, Whitman S, Klein RD, Fischer SM, Holman TR
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Activation of the unfolded protein response is associated with favorable prognosis in acute myeloid leukemia
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An immunosurveillance mechanism controls cancer cell ploidy
Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, Galluzzi L, Adjemian S, Kepp O, Niso-Santano M, Shen S, Mariño G, Criollo A, Boilève A, Job B, Ladoire S, Ghiringhelli F, Sistigu A, Yamazaki T, Rello-Varona S, Locher C, Poirier-Colame V, Talbot M, Valent A, Berardinelli F, Antoccia A, Ciccosanti F, Fimia GM, Piacentini M, Fueyo A, Messina NL, Li M, Chan CJ, Sigl V, Pourcher G, Ruckenstuhl C, Carmona-Gutierrez D, Lazar V, Penninger JM, Madeo F, López-Otín C, Smyth MJ, Zitvogel L, Castedo M, Kroemer G
Science 2012 Sep 28;337(6102):1678-84
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Overexpression of calreticulin contributes to the development and progression of pancreatic cancer
Sheng W, Chen C, Dong M, Zhou J, Liu Q, Dong Q, Li F
J Cell Physiol 2014 Jul;229(7):887-97
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Calreticulin promotes migration and invasion of esophageal cancer cells by upregulating neuropilin-1 expression via STAT5A
Shi F, Shang L, Pan BQ, Wang XM, Jiang YY, Hao JJ, Zhang Y, Cai Y, Xu X, Zhan QM, Wang MR
Clin Cancer Res 2014 Dec 1;20(23):6153-62
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JAK2, CALR, and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms
Shirane S, Araki M, Morishita S, Edahiro Y, Takei H, Yoo Y, Choi M, Sunami Y, Hironaka Y, Noguchi M, Koike M, Noda N, Ohsaka A, Komatsu N
Haematologica 2015 Feb;100(2):e46-8
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Proteomic analysis of breast cancer tissues to identify biomarker candidates by gel-assisted digestion and label-free quantification methods using LC-MS/MS
Song MN, Moon PG, Lee JE, Na M, Kang W, Chae YS, Park JY, Park H, Baek MC
Arch Pharm Res 2012 Oct;35(10):1839-47
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Panel of Urinary Diagnostic Markers for Non-Invasive Detection of Primary and Recurrent Urothelial Urinary Bladder Carcinoma
Soukup V, Kalousová M, Capoun O, Sobotka R, Breyl Z, Pešl M, Zima T, Hanuš T
Urol Int 2015;95(1):56-64
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CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons
Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, Maffioli M, Caramazza D, Passamonti F, Pardanani A
Leukemia 2014 Jul;28(7):1472-7
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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 MG, Mosnier JF, Laboisse CL
Oncol Rep 2007 May;17(5):1101-7
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Calreticulin expression is reduced in high-grade ovarian serous carcinoma effusions compared with primary tumors and solid metastases
Vaksman O, Davidson B, Tropé C, Reich R
Hum Pathol 2013 Dec;44(12):2677-83
PMID 24060004
 
Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells
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Cell Death Differ 2004 Mar;11(3):321-30
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Nerve growth factor induces the expression of chaperone protein calreticulin in human epithelial ovarian cells
Vera C, Tapia V, Kohan K, Gabler F, Ferreira A, Selman A, Vega M, Romero C
Horm Metab Res 2012 Jul;44(8):639-43
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Two-dimensional electrophoresis and immunohistochemical study of calreticulin in colorectal adenocarcinoma and mirror biopsies
Vougas K, Gaitanarou E, Marinos E, Kittas C, Voloudakis-Baltatzis IE
J BUON 2008 Jan-Mar;13(1):101-7
PMID 18404795
 
PTP1B contributes to calreticulin-induced metastatic phenotypes in esophageal squamous cell carcinoma
Wang XM, Shang L, Zhang Y, Hao JJ, Shi F, Luo W, Zhang TT, Wang BS, Yang Y, Liu ZH, Zhan QM, Wang MR
Mol Cancer Res 2013 Sep;11(9):986-94
PMID 23814025
 
Proteomic differential display identifies upregulated vinculin as a possible biomarker of pancreatic cancer
Wang Y, Kuramitsu Y, Ueno T, Suzuki N, Yoshino S, Iizuka N, Zhang X, Akada J, Oka M, Nakamura K
Oncol Rep 2012 Nov;28(5):1845-50
PMID 22940724
 
Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia
Wemeau M, Kepp O, Tesnière A, Panaretakis T, Flament C, De Botton S, Zitvogel L, Kroemer G, Chaput N
Cell Death Dis 2010 Dec 2;1:e104
PMID 21368877
 
Calreticulin Regulates VEGF-A in Neuroblastoma Cells
Weng WC, Lin KH, Wu PY, Lu YC, Weng YC, Wang BJ, Liao YF, Hsu WM, Lee WT, Lee H
Mol Neurobiol 2015 Aug;52(1):758-70
PMID 25288151
 
Frequency and molecular characteristics of calreticulin gene (CALR) mutations in patients with JAK2 -negative myeloproliferative neoplasms
Wojtaszewska M, Iwońa M, Lewandowski K
Acta Haematol 2015;133(2):193-8
PMID 25323779
 
Proteome analysis of human androgen-independent prostate cancer cell lines: variable metastatic potentials correlated with vimentin expression
Wu M, Bai X, Xu G, Wei J, Zhu T, Zhang Y, Li Q, Liu P, Song A, Zhao L, Gang C, Han Z, Wang S, Zhou J, Lu Y, Ma D
Proteomics 2007 Jun;7(12):1973-83
PMID 17566973
 
The mutation profile of JAK2 and CALR in Chinese Han patients with Philadelphia chromosome-negative myeloproliferative neoplasms
Wu Z, Zhang X, Xu X, Chen Y, Hu T, Kang Z, Li S, Wang H, Liu W, Ma X, Guan M
J Hematol Oncol 2014 Jul 15;7:48
PMID 25023898
 
A comparative proteomic study identified calreticulin and prohibitin up-regulated in adrenocortical carcinomas
Yang MS, Wang HS, Wang BS, Li WH, Pang ZF, Zou BK, Zhang X, Shi XT, Mu DB, Zhang DX, Gao YS, Sun XW, Xia SJ
Diagn Pathol 2013 Apr 15;8:58
PMID 23587357
 
Nuclear matrix of calreticulin in hepatocellular carcinoma
Yoon GS, Lee H, Jung Y, Yu E, Moon HB, Song K, Lee I
Cancer Res 2000 Feb 15;60(4):1117-20
PMID 10706133
 
Identification of differentially expressed proteins between human hepatoma and normal liver cell lines by two-dimensional electrophoresis and liquid chromatography-ion trap mass spectrometry
Yu LR, Zeng R, Shao XX, Wang N, Xu YH, Xia QC
Electrophoresis 2000 Aug;21(14):3058-68
PMID 11001323
 
Calreticulin and cancer
Zamanian M, Veerakumarasivam A, Abdullah S, Rosli R
Pathol Oncol Res 2013 Apr;19(2):149-54
PMID 23392843
 
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 Apr 15;59(8):1896-902
PMID 10213498
 
Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway
Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G
Clin Cancer Res 2010 Jun 15;16(12):3100-4
PMID 20421432
 
Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells
Zu S, Ma W, Xiao P, Cui Y, Ma T, Zhou C, Zhang H
Urol Int 2015;95(1):114-9
PMID 25999365
 

Citation

This paper should be referenced as such :
CALR (calreticulin);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CALRID904ch19p13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Adenocarcinoma


External links

Nomenclature
HGNC (Hugo)CALR   1455
LRG (Locus Reference Genomic)LRG_828
Cards
AtlasCALRID904ch19p13.txt
Entrez_Gene (NCBI)CALR  811  calreticulin
AliasesCRT; HEL-S-99n; RO; SSA; 
cC1qR
GeneCards (Weizmann)CALR
Ensembl hg19 (Hinxton)ENSG00000179218 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000179218 [Gene_View]  chr19:12938600-12944490 [Contig_View]  CALR [Vega]
ICGC DataPortalENSG00000179218
TCGA cBioPortalCALR
AceView (NCBI)CALR
Genatlas (Paris)CALR
WikiGenes811
SOURCE (Princeton)CALR
Genetics Home Reference (NIH)CALR
Genomic and cartography
GoldenPath hg38 (UCSC)CALR  -     chr19:12938600-12944490 +  19p13.13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CALR  -     19p13.13   [Description]    (hg19-Feb_2009)
EnsemblCALR - 19p13.13 [CytoView hg19]  CALR - 19p13.13 [CytoView hg38]
Mapping of homologs : NCBICALR [Mapview hg19]  CALR [Mapview hg38]
OMIM109091   187950   254450   
Gene and transcription
Genbank (Entrez)AB451408 AF087986 AK130190 AK223060 AK295230
RefSeq transcript (Entrez)NM_004343
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CALR
Cluster EST : UnigeneHs.515162 [ NCBI ]
CGAP (NCI)Hs.515162
Alternative Splicing GalleryENSG00000179218
Gene ExpressionCALR [ NCBI-GEO ]   CALR [ EBI - ARRAY_EXPRESS ]   CALR [ SEEK ]   CALR [ MEM ]
Gene Expression Viewer (FireBrowse)CALR [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)811
GTEX Portal (Tissue expression)CALR
Protein : pattern, domain, 3D structure
UniProt/SwissProtP27797   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP27797  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP27797
Splice isoforms : SwissVarP27797
PhosPhoSitePlusP27797
Domaine pattern : Prosite (Expaxy)CALRETICULIN_1 (PS00803)    CALRETICULIN_2 (PS00804)    CALRETICULIN_REPEAT (PS00805)    ER_TARGET (PS00014)   
Domains : Interpro (EBI)Calret/calnex    Calret/calnex_CS    Calreticulin    Calreticulin/calnexin_P_dom    ConA-like_dom   
Domain families : Pfam (Sanger)Calreticulin (PF00262)   
Domain families : Pfam (NCBI)pfam00262   
Conserved Domain (NCBI)CALR
DMDM Disease mutations811
Blocks (Seattle)CALR
PDB (SRS)2CLR    3DOW    3POS    3POW    5LK5   
PDB (PDBSum)2CLR    3DOW    3POS    3POW    5LK5   
PDB (IMB)2CLR    3DOW    3POS    3POW    5LK5   
PDB (RSDB)2CLR    3DOW    3POS    3POW    5LK5   
Structural Biology KnowledgeBase2CLR    3DOW    3POS    3POW    5LK5   
SCOP (Structural Classification of Proteins)2CLR    3DOW    3POS    3POW    5LK5   
CATH (Classification of proteins structures)2CLR    3DOW    3POS    3POW    5LK5   
SuperfamilyP27797
Human Protein AtlasENSG00000179218
Peptide AtlasP27797
HPRD00169
IPIIPI00020599   IPI01013746   
Protein Interaction databases
DIP (DOE-UCLA)P27797
IntAct (EBI)P27797
FunCoupENSG00000179218
BioGRIDCALR
STRING (EMBL)CALR
ZODIACCALR
Ontologies - Pathways
QuickGOP27797
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  acrosomal vesicle  complement component C1q binding  glycoprotein binding  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  DNA binding  RNA binding  mRNA binding  integrin binding  iron ion binding  calcium ion binding  calcium ion binding  protein binding  extracellular region  proteinaceous extracellular matrix  extracellular space  extracellular space  intracellular  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum lumen  endoplasmic reticulum lumen  smooth endoplasmic reticulum  Golgi apparatus  cytosol  polysome  focal adhesion  regulation of transcription, DNA-templated  protein folding  protein export from nucleus  cellular calcium ion homeostasis  receptor-mediated endocytosis  spermatogenesis  zinc ion binding  positive regulation of cell proliferation  external side of plasma membrane  cell surface  positive regulation of endothelial cell migration  positive regulation of gene expression  membrane  negative regulation of translation  negative regulation of translation  protein maturation by protein folding  carbohydrate binding  phagocytic vesicle membrane  cortical actin cytoskeleton organization  ubiquitin protein ligase binding  response to estradiol  sarcoplasmic reticulum lumen  endoplasmic reticulum-Golgi intermediate compartment membrane  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  peptide binding  response to drug  hormone binding  MHC class I peptide loading complex  glucocorticoid receptor signaling pathway  regulation of apoptotic process  protein binding involved in protein folding  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  perinuclear region of cytoplasm  androgen receptor binding  positive regulation of phagocytosis  protein stabilization  protein stabilization  unfolded protein binding  chaperone binding  sequestering of calcium ion  cardiac muscle cell differentiation  chaperone-mediated protein folding  extracellular exosome  negative regulation of cell cycle arrest  cellular response to lithium ion  integral component of lumenal side of endoplasmic reticulum membrane  endocytic vesicle lumen  cellular senescence  positive regulation of substrate adhesion-dependent cell spreading  negative regulation of trophoblast cell migration  positive regulation of NIK/NF-kappaB signaling  vesicle fusion with endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane  positive regulation of dendritic cell chemotaxis  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  acrosomal vesicle  complement component C1q binding  glycoprotein binding  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  DNA binding  RNA binding  mRNA binding  integrin binding  iron ion binding  calcium ion binding  calcium ion binding  protein binding  extracellular region  proteinaceous extracellular matrix  extracellular space  extracellular space  intracellular  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum lumen  endoplasmic reticulum lumen  smooth endoplasmic reticulum  Golgi apparatus  cytosol  polysome  focal adhesion  regulation of transcription, DNA-templated  protein folding  protein export from nucleus  cellular calcium ion homeostasis  receptor-mediated endocytosis  spermatogenesis  zinc ion binding  positive regulation of cell proliferation  external side of plasma membrane  cell surface  positive regulation of endothelial cell migration  positive regulation of gene expression  membrane  negative regulation of translation  negative regulation of translation  protein maturation by protein folding  carbohydrate binding  phagocytic vesicle membrane  cortical actin cytoskeleton organization  ubiquitin protein ligase binding  response to estradiol  sarcoplasmic reticulum lumen  endoplasmic reticulum-Golgi intermediate compartment membrane  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  peptide binding  response to drug  hormone binding  MHC class I peptide loading complex  glucocorticoid receptor signaling pathway  regulation of apoptotic process  protein binding involved in protein folding  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  perinuclear region of cytoplasm  androgen receptor binding  positive regulation of phagocytosis  protein stabilization  protein stabilization  unfolded protein binding  chaperone binding  sequestering of calcium ion  cardiac muscle cell differentiation  chaperone-mediated protein folding  extracellular exosome  negative regulation of cell cycle arrest  cellular response to lithium ion  integral component of lumenal side of endoplasmic reticulum membrane  endocytic vesicle lumen  cellular senescence  positive regulation of substrate adhesion-dependent cell spreading  negative regulation of trophoblast cell migration  positive regulation of NIK/NF-kappaB signaling  vesicle fusion with endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane  positive regulation of dendritic cell chemotaxis  
Pathways : BIOCARTANFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]   
Pathways : KEGGProtein processing in endoplasmic reticulum    Phagosome    Antigen processing and presentation    Chagas disease (American trypanosomiasis)    HTLV-I infection   
REACTOMEP27797 [protein]
REACTOME PathwaysR-HSA-983170 [pathway]   
NDEx NetworkCALR
Atlas of Cancer Signalling NetworkCALR
Wikipedia pathwaysCALR
Orthology - Evolution
OrthoDB811
GeneTree (enSembl)ENSG00000179218
Phylogenetic Trees/Animal Genes : TreeFamCALR
HOVERGENP27797
HOGENOMP27797
Homologs : HomoloGeneCALR
Homology/Alignments : Family Browser (UCSC)CALR
Gene fusions - Rearrangements
Fusion : MitelmanADGRF4/CALR [6p12.3/19p13.2]  [t(6;19)(p12;p13)]  
Fusion : MitelmanCALR/ACACA [19p13.2/17q12]  [t(17;19)(q12;p13)]  
Fusion : MitelmanCALR/BRD2 [19p13.2/6p21.32]  [t(6;19)(p21;p13)]  
Fusion : MitelmanH19/CALR [11p15.5/19p13.2]  [t(11;19)(p15;p13)]  
Fusion: TCGACALR 19p13.2 BRD2 6p21.32 PRAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCALR [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CALR
dbVarCALR
ClinVarCALR
1000_GenomesCALR 
Exome Variant ServerCALR
ExAC (Exome Aggregation Consortium)CALR (select the gene name)
Genetic variants : HAPMAP811
Genomic Variants (DGV)CALR [DGVbeta]
DECIPHERCALR [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCALR 
Mutations
ICGC Data PortalCALR 
TCGA Data PortalCALR 
Broad Tumor PortalCALR
OASIS PortalCALR [ Somatic mutations - Copy number]
Cancer Gene: CensusCALR 
Somatic Mutations in Cancer : COSMICCALR  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCALR
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CALR
DgiDB (Drug Gene Interaction Database)CALR
DoCM (Curated mutations)CALR (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CALR (select a term)
intoGenCALR
NCG5 (London)CALR
Cancer3DCALR(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM109091    187950    254450   
Orphanet3599    8745   
MedgenCALR
Genetic Testing Registry CALR
NextProtP27797 [Medical]
TSGene811
GENETestsCALR
Target ValidationCALR
Huge Navigator CALR [HugePedia]
snp3D : Map Gene to Disease811
BioCentury BCIQCALR
ClinGenCALR
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD811
Chemical/Pharm GKB GenePA26046
Clinical trialCALR
Miscellaneous
canSAR (ICR)CALR (select the gene name)
Probes
Litterature
PubMed390 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCALR
EVEXCALR
GoPubMedCALR
iHOPCALR
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 30 11:02:22 CEST 2017

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