Disease relevance of CALR

• Nonglycosylated HIV envelope protein was not associated with calreticulin, suggesting a requirement for N-linked oligosaccharides on newly synthesized proteins as has been reported for calnexin [1].
• Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells [2].
• Complete congenital heart block is associated with increased autoantibody titers against calreticulin [3].
• Accordingly, quantitative immunoblot analysis showed that Calreticulin expression was significantly lower in human colonic cancer cell lines than in preparations of isolated human normal colonic epithelial cells [4].
• Recent studies, based on proteomic approaches on whole tissue samples containing both neoplastic and non-neoplastic cells, have shown alterations of Calreticulin expression in colon carcinomas, albeit with divergent results [4].

Psychiatry related information on CALR

• We, therefore, examined the localization and expression of CRT, Bip and their mRNA by immunohistochemistry, Western blot, in situ hybridization and semiquantitative reverse transcription polymerase chain reaction (RT-PCR) in both neurologically normal and Alzheimer's disease (AD) brains [5].
• Calreticulin, a molecular chaperone involved in the folding of endoplasmic reticulum synthesized proteins, is also a shock protein induced by heat, food deprivation, and chemical stress [6].
• RT84 Id was positively associated with antibodies to Sm-D peptide 1-20 and to Ro/SSA 60 kD peptide 304-324, but negatively associated with anti-dsDNA activity [7].
• Subjective sleep quality and the total score of the Self-Assessment Scale for Sleep and Awakening Quality (SSA) were deteriorated as were evening and morning well-being, mood, affectivity and drowsiness [8].
• Stimulus-synchronized (SSA) and response-synchronized (RSA) averages were computed for correct trials only in association with the first (Q1) and fourth (Q4) reaction time (RT) quartiles [9].

High impact information on CALR

• Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation [10].
• Further deglucosylation of the oligosaccharides by glucosidase II liberates glycoproteins from their calnexin/calreticulin anchors [11].
• Calreticulin exposure dictates the immunogenicity of cancer cell death [12].
• Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice [12].
• Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation [13].

Chemical compound and disease context of CALR

• Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin [1].
• The present review summarizes the results of a legume lectin study as well as those obtained from a similar analysis carried out here on the animal lectins, namely galectins, pentraxins, calnexin, calreticulin and rhesus rotavirus Vp4 sialic-acid-binding domain [14].
• However, the intensity of NBT response in stimulated lupus lymphocytes was positively correlated with the presence of serum SSA (Ro) antibody [15].
• Calreticulin expression is associated with androgen regulation of the sensitivity to calcium ionophore-induced apoptosis in LNCaP prostate cancer cells [16].
• Homozygous C2 deficiency, lupus erythematosus, and anti-Ro (SSA) antibodies [17].

Biological context of CALR

• Calreticulin Is a receptor for nuclear export [18].
• Previous studies linking CRT to downregulation of steroid hormone receptor function led us to examine its potential role in nuclear export of the glucocorticoid receptor (GR) [18].
• We found that CRT mediates nuclear export of GR in permeabilized cell, microinjection, and transfection assays [18].
• Folding of insulin receptor monomers is facilitated by the molecular chaperones calnexin and calreticulin and impaired by rapid dimerization [19].
• To study the role of calreticulin in Ca(2+) homeostasis and apoptosis, we generated cells inducible for full-length or truncated calreticulin and measured Ca(2+) signals within the cytosol, the endoplasmic reticulum (ER), and mitochondria with "cameleon" indicators [20].

Anatomical context of CALR

• We demonstrated previously that calreticulin (CRT) interacts with the lumenal COOH-terminal sequence of sarco endoplasmic reticulum (ER) calcium ATPase (SERCA) 2b to inhibit Ca2+ oscillations [21].
• All neutrophils expressed calreticulin with a unimodal distribution [22].
• Little if any H chain was detected in association with TAP and calreticulin in the beta 2m- cell line Daudi [23].
• We now report that calreticulin on the cell surface mediates focal adhesion disassembly by thrombospondin/hep I [24].
• A 60-kDa protein from endothelial cell detergent extracts has homology and immunoreactivity to calreticulin, binds a hep I affinity column, and neutralizes thrombospondin/hep I-mediated focal adhesion disassembly [24].

Associations of CALR with chemical compounds

• Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP [25].
• An inhibitor of glucose trimming, castanospermine (CST), abolished binding to Cnx/Crt but also unexpectedly accelerated receptor homodimerization resulting in misfolded oligomeric proreceptors whose processing was delayed and cell surface expression was also decreased by approximately 30% [19].
• CRT defines a new export pathway that may regulate the transcriptional activity of steroid hormone receptors [18].
• The data are consistent with a model in which the release of peptide-loaded major histocompatibility complex class I molecules from calreticulin, induced by deglucosylation of the heavy chain N-linked glycan, signals the dissociation of the complex [26].
• Nonglycosylated MPO precursors synthesized in the presence of tunicamycin did not interact with CRT [27].

Physical interactions of CALR

• In addition, we report that ERp27 is bound by ERp57 both in vitro and in vivo by a similar mechanism by which ERp57 binds calreticulin [28].
• Peptides spanning aa 19-36 (RWIESKHKSDFGKFVLSS) blocked hep I-stimulated focal adhesion disassembly, indicating that the TSP/hep I-binding site is located to this sequence in calreticulin [29].
• Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell [30].
• We show that APP binds transiently to Crt in a manner that is pH, divalent cation, and N-linked glycosylation-dependent [31].
• Calreticulin is an endoplasmic reticulum luminal calcium-binding chaperone involved in various cellular functions and is a ligand for the scavenger receptor CD91 [4].

Co-localisations of CALR

• Immunofluorescence and confocal microscopy demonstrated that ecto-calreticulin co-localized with a fraction of CD59 at the cell surface [22].
• NOX2 and NOX4 co-localized with the endoplasmic reticulum (ER) marker calreticulin [32].
• Fractionation of cell extracts on discontinuous sucrose gradients and indirect immunofluorescence indicate that CAML co-localizes with sarcoplasmic/endoplasmic reticulum calcium/ATPase-2 and calreticulin at membrane-bound cytosolic vesicles [33].

Regulatory relationships of CALR

• Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain [30].
• CD91 was co-expressed with Calreticulin in both normal colonic epithelial cells and pericryptic myofibroblasts [4].
• Calreticulin promotes folding/dimerization of human lipoprotein lipase expressed in insect cells (sf21) [34].
• Human Dicer expressed in mammalian cells colocalized with calreticulin, a resident protein of the endoplasmic reticulum [35].
• Calreticulin Represses E-cadherin Gene Expression in Madin-Darby Canine Kidney Cells via Slug [36].

Other interactions of CALR

• Here, we show that the related chaperone, calreticulin, binds human class I-beta 2m dimers prior to peptide loading [25].
• Together, these studies demonstrate a chaperone function for Cnx/Crt in HIR folding in vivo and also provide evidence that folding efficiency and homodimerization are counterbalanced [19].
• Heavy chains were also isolated from Raji cells in multimolecular complexes (peptide loading complexes) containing the transporter associated with antigen processing, tapasin and ERp57 with and without the lectin-like folding chaperone, calreticulin [26].
• The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters [37].
• Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin [24].

Analytical, diagnostic and therapeutic context of CALR

• Calreticulin on the cell surface was confirmed by biotinylation, confocal microscopy, and by fluorescence-activated cell sorting analyses [24].
• DNA footprint and gel shift analysis on the CR 5'-flanking region demonstrates an area that is bound by protein found in human but not murine nuclear extracts [37].
• An appreciation that the adaptors for ecto-calreticulin are GPI-anchored will provide a framework for understanding any common features underlying ecto-calreticulin ligation [22].
• Sequential immunoprecipitations provided evidence for the existence of ternary complexes of gp160, calreticulin, and calnexin [1].
• The expression of ecto-calreticulin on purified human neutrophils did not result from contamination by soluble or intracellular calreticulin released during cell fractionation because it was expressed on circulating neutrophils, and the expression did not increase significantly with neutrophil isolation [22].

References