CALR

Official Full Name

calreticulin

Organism

Homo sapiens

GeneID

811

Background

Calreticulin is a highly conserved chaperone protein which resides primarily in the endoplasmic reticulum, and is involved in a variety of cellular processes, among them, cell adhesion. Additionally, it functions in protein folding quality control and calcium homeostasis. Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin. Recurrent mutations in calreticulin have been linked to various neoplasms, including the myeloproliferative type.[provided by RefSeq, May 2020]

Synonyms

RO; CRT; SSA; CALR1; cC1qR; HEL-S-99n;

Protein Sequence

MLLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQDARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIMFGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDYKGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVTKAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQAKDEL

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Detailed Information

Calreticulin (CALR) has emerged as a fascinating protein with diverse functions that extend far beyond its well-known role as an endoplasmic reticulum (ER) chaperone. Recent studies reveal its important role in cancer biology, where it interacts at the junction of immunosurveillance, malignant transformation, and cellular stress responses. Deeper knowledge of CALR's activities makes it abundantly evident that this protein serves both tumor-suppressive and, in certain cases, tumor-promoting roles.

Fundamental Structure and Functions of CALR

Fundamentally CALR is a highly conserved calcium-binding chaperone mostly found in the ER lumen. Its three separate domains include an N-terminal lectin-like globular domain, a proline-rich middle domain, and a very acidic C-terminal area. Together, these domains let CALR engage in many physiological functions including calcium homeostasis, cell adhesion, and protein folding quality control. The capacity of the protein to move across many cellular compartments—including the nucleus—suggests its participation in transcription control as well.

Figure 1 describes the contrasting roles of wild-type calreticulin in protein folding and calcium buffering in the ER versus the oncogenic signaling and transport disruptions caused by cancer-associated calreticulin mutations. Figure 1. Contrasting functions of wild-type and mutant calreticulin in cancer biology. (Fucikova J et al., 2021)

CALR's Role in Antigen Presentation

One of CALR's most fascinating roles is that of a fundamental component of the peptide-loading complex (PLC), which is necessary for appropriate antigen presentation on MHC Class I molecules. CALR guarantees the assembly of MHC Class I heavy chains with beta-2 microglobulin and the loading of antigenic peptides working in tandem with other proteins like PDIA3 (also known as ERp57), tapasin, and TAP1/2. Because it presents intracellular antigens to cytotoxic T lymphocytes, enabling the immune system to recognize and destroy potentially harmful cells including those undergoing malignant transformation, this mechanism is very essential for immunological surveillance.

CALR and Immunogenic Cell Death

But when we examine CALR's function in immunogenic cell death (ICD), the narrative of CALR in cancer biology veers unexpectedly. CALR may be exposed on the cell surface when cancer cells experience various types of stress or death. Here, it functions as a potent "eat me" signal to antigen-presenting cells, especially dendritic cells. This exposure is a well-coordinated event including the integrated stress response and particular molecular machinery, not a simple passive process. CALR's translocation to the cell surface calls on the phosphorylation of eIF2α by PERK, the participation of pro-apoptotic proteins like BAX and BAK, and the anterograde ER to Golgi transport mechanism.

CALR and Anti-Tumor Immunity

Surface-exposed CALR's immunostimulating properties are mostly mediated by its contact with LRP1 (CD91), on antigen-presenting cells. But CD47, acting as a "don't eat me" signal via its interaction with SIRPα on phagocytes, may offset this pro-phagocytic signal. The destiny of the dying cell and its capacity to induce an immune response depends finally on the balance between these conflicting signals.

Fascinatingly, new studies have shown that CALR contact with cancer cells may have implications beyond only enhancing phagocytosis. High levels of surface CALR have been linked in acute myeloid leukemia (AML) to the increase of CD11b+CD14+ myeloid cells able to trans-present IL-15 to natural killer cells, hence improving anti-tumor immunity. Moreover, CALR exposure has been associated with type I interferon signaling; the exact processes behind this association are still unknown.

Clinical Significance of CALR

Numerous research looking at CALR's prognostic value has made clear its therapeutic relevance in cancer. High CALR expression is linked in many solid tumors to better patient outcomes, usually linked with evidence of active anti-tumor immunity. For colorectal carcinoma, for example, greater CALR levels correspond with enhanced infiltration by memory T cells; in non-small cell lung cancer, on the other hand, they are linked with larger numbers of dendritic cells and T helper 1 cells in the tumor microenvironment.

Still, the link between CALR expression and cancer prognosis is complex. High CALR levels have been linked in various forms of tumors to bad outcomes. The dual nature of CALR's activities—while its immunostimulatory properties might boost anti-tumor immunity—its intracellular roles in calcium homeostasis and integrin signaling may help tumor development in certain circumstances, hence explaining this seeming paradox.

CALR Gene Mutations and Cancer

Finding repeated mutations in the CALR gene—especially in myeloproliferative neoplasms (MPNs)—has complicated our knowledge of its function in cancer even further. Most usually affecting exon 9, these mutations produce a mutant protein devoid of ER retention signal that may form stable complexes with the thrombopoietin receptor MPL, hence activating JAK2 signaling. Fascinatingly, while the immunobiological reason for this result is still unknown, MPN patients with CALR mutations usually have a better prognosis than those with wild-type CALR.

Recent studies further show that certain CALR mutations might produce higher protein secretion, which can function as a decoy to overload CALR receptors on immune cells, hence possibly undermining immunosurveillance. Although they are somewhat infrequent in solid tumors, occurring in just 1-2% of cases, such mutations draw attention to the many ways in which changes in CALR function could affect cancer development.

Potential Applications of CALR in Cancer Treatment

Our knowledge of CALR biology has therapeutic ramifications of great importance. Many techniques are under investigation to either harness or offset CALR's effects in cancer therapy. These include the search for therapeutic vaccinations aiming at mutant CALR in MPNs and the creation of CD47-blocking antibodies to improve the pro-phagocytic effects of surface-exposed CALR. Furthermore, certain chemotherapeutic drugs' capacity to cause CALR exposure in dying cancer cells might help to explain their effectiveness by stimulating anti-tumor immune responses.

Future Research Directions

Many uncertainties remain even as we work to understand CALR's many functions in cancer biology. How can we balance the contradicting prognostic consequences of CALR expression in many cancer forms? In a particular situation, what decides whether CALR will behave essentially as a tumor suppressor or promoter? How may our knowledge of CALR biology be most used to create more successful cancer treatments?

References:

Fucikova J, Spisek R, Kroemer G, Galluzzi L. Calreticulin and cancer. Cell Res. 2021;31(1):5-16.
Papadopoulos N, Nédélec A, Derenne A, et al. Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation. Nat Commun. 2023 Apr 5;14(1):1881.
Tayyeb A, Dihazi GH, Tampe B, et al. Calreticulin Shortage Results in Disturbance of Calcium Storage, Mitochondrial Disease, and Kidney Injury. Cells. 2022 Apr 13;11(8):1329.

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