Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion

Coppolino, Marc G.; Woodside, Michael; Demaurex, Nicolas; Grinstein, Sergio; St‐Arnaud, René; Dedhar, Shoukat

doi:10.1038/386843a0

Cited by 365 publications

(303 citation statements)

References 27 publications

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“…Akt activation or inactivation has been reported to play an important role in CRT-associated apoptosis (Kageyama et al, 2002;Okunaga et al, 2006;Lim et al, 2008). CRT-deficient mice show embryonic lethal characteristics due to changes in cell adhesiveness and impairment of cardiac development and function (Coppolino et al, 1997;Rauch et al, 2000;Mesaeli and Phillipson, 2004). CRT may have an important role in the development and/or progression of various human cancers: overexpression of CRT has been found in breast ductal carcinoma (Bini et al, 1997;Chahed et al, 2005), prostate adenocarcinoma (Alaiya et al, 2000), hepatocellular carcinoma (Kim et al, 2004) and colon cancer (Vougas et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

Yang

et al. 2009

Oncogene

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We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impaired cell migration, invasion and resistance to anoikis. Notably, CRT downregulation decreased the expression of Cortactin (CTTN), which has been previously reported as a candidate oncogene associated with anoikis through the PI3K-Akt pathway. In addition, Akt phosphorylation was abolished after CRT downregulation and its activation can be refreshed by CRT upregulation, suggesting that CRT-enhanced cell resistance to anoikis through the CRT-CTTN-PI3K-Akt pathway. Moreover, the CTTN mRNA level was decreased in CRT-siRNA cells, coupled with the inactivation of STAT3. Expression of both CTTN and p-STAT3 was reduced in tumor cells following incubation with the JAK-specific inhibitor, AG490. Chromatin immunoprecipitation assay showed direct binding of p-STAT3 to the conservative STAT3-binding sequences in CTTN promoter. Furthermore, overexpression of CTTN in CRT-downregulated ESCC cells restored its motility and resistance to anoikis. This study not only reveals a role of CRT in motility promotion and anoikis resistance in ESCC cells, but also identifies CRT as an upstream regulator in the CRT-STAT3-CTTNAkt pathway.

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Section: Introductionmentioning

confidence: 99%

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

Yang

et al. 2009

Oncogene

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“…5,7 CRT is a Ca 2 þ -binding protein with two sites (with high and low capacity) for buffering Ca 2 þ , thus affecting Ca 2 þ signaling and Ca 2 þ homeostasis. [8][9][10] CRT is a soluble protein Received 31.1.08; revised 17.3.08; accepted 31.3.08; Edited by P Bouillet; published online 9.5.08 …”

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confidence: 99%

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

et al. 2008

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The exposure of calreticulin (CRT) on the plasma membrane can precede anthracycline-induced apoptosis and is required for cell death to be perceived as immunogenic. Mass spectroscopy, immunofluorescence and immunoprecipitation experiments revealed that CRT co-translocates to the surface with another endoplasmic reticulum-sessile protein, the disulfide isomerase ERp57. The knockout and knockdown of CRT or ERp57 inhibited the anthracycline-induced translocation of ERp57 or CRT, respectively. CRT point mutants that fail to interact with ERp57 were unable to restore ERp57 translocation upon transfection into crt À/À cells, underscoring that a direct interaction between CRT and ERp57 is strictly required for their co-translocation to the surface. ERp57 low tumor cells generated by retroviral introduction of an ERp57-specific shRNA exhibited a normal apoptotic response to anthracyclines in vitro, yet were resistant to anthracycline treatment in vivo. Moreover, ERp57 low cancer cells (which failed to expose CRT) treated with anthracyclines were unable to elicit an anti-tumor response in conditions in which control cells were highly immunogenic. The failure of ERp57 low cells to elicit immune responses and to respond to chemotherapy could be overcome by exogenous supply of recombinant CRT protein. These results indicate that tumors that possess an intrinsic defect in the CRT-translocating machinery become resistant to anthracycline chemotherapy due to their incapacity to elicit an anticancer immune response. The conventional treatment of cancer relies upon radiotherapy and chemotherapy, two procedures that supposedly mediate their therapeutic effects solely by intrinsic mechanisms of tumor cell death and without direct participation by the host immune system. Nevertheless, there are specific circumstances in which conventional anti-cancer treatments can induce a modality of cell death that is immunogenic, whereby dying cells elicit a tumor-specific immune response culminating in elimination of tumor cells. Although most chemotherapeutic agents kill tumor cells through a morphologically indistinguishable apoptotic pathway, they differ in their capacity to stimulate immunogenic as opposed to nonimmunogenic cell death. 1 Recently, we reported that tumor cells undergoing immunogenic cell death translocate intracellular calreticulin (endo-CRT) to their plasma membrane (PM) surface (ecto-CRT), facilitating tumor cell recognition and engulfment by dendritic cells (DC) and subsequent T-cellmediated elimination of the tumor. 2 Accordingly, anthracyclines and g-irradiation, which elicit immunogenic cell death, induce CRT exposure whereas other proapoptotic agents that induce non-immunogenic cell death fail to induce ecto-CRT. [2][3][4] Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, whereas addition of exogenous CRT or enforced surface exposure of CRT by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. 2,4 An additional signal emitted during ...

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“…More recently, we demonstrated that murine embryonic stem cells genetically lacking calreticulin exhibit severely impaired integrin-mediated adhesion and calcium influx [31]. In the present study, we have used PC-3 prostatic carcinoma cells to demonstrate that calreticulin interacts transiently with integrins as the cells attach and spread on ECM proteins.…”

Section: Introductionmentioning

confidence: 62%

“…It was also found that this induced interaction between the integrin and calreticulin is important for the α # β " -mediated adhesion of Jurkat cells to collagen type I [30]. More recently, we reported on the development of calreticulin knock-out murine embryonic stem cells, and found that calreticulin is essential for integrin-mediated adhesion and calcium signalling [31]. The results of the present study suggest that calreticulin binds to integrins as they first become activated, either by antibody stimulation or by encountering ECM proteins.…”

Section: Discussionmentioning

confidence: 84%

“…The observations that the interaction between calreticulin and integrins can be influenced by phosphorylation and dephosphorylation events strengthen further the concept that this interaction is closely associated with changes in integrin activity. In the light of these findings, together with the observation that calreticulin is essential for both integrinmediated adhesion and Ca# + influx [31], it is reasonable to conclude that calreticulin both responds to and is necessary for integrin activity, and that the interaction between integrins and calreticulin is an important mediator of transmembrane signalling. …”

Section: Discussionmentioning

confidence: 91%

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Ligand-specific, transient interaction between integrins and calreticulin during cell adhesion to extracellular matrix proteins is dependent upon phosphorylation/dephosphorylation events

Coppolino

Dedhar

1999

Biochemical Journal

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As transmembrane heterodimers, integrins bind to both extracellular ligands and intracellular proteins. We are currently investigating the interaction between integrins and the intracellular protein calreticulin. A prostatic carcinoma cell line (PC-3) was used to demonstrate that calreticulin can be found in the α3 immunoprecipitates of cells plated on collagen type IV, but not when plated on vitronectin. Conversely, αv immunoprecipitates contained calreticulin only when cells were plated on vitronectin, i.e. not when plated on collagen IV. The interactions between these integrins and calreticulin were independent of actin cytoskeleton assembly and were transient, being maximal approx. 10-30 min after the cells came into contact with the substrates prior to complete cell spreading and formation of firm adhesive contacts. We demonstrate that okadaic acid, an inhibitor of intracellular serine/threonine protein phosphatases, inhibited the α3β1-mediated adhesion of PC-3 cells to collagen IV and the α2β1-mediated attachment of Jurkat cells to collagen I. This inhibition by okadaic acid was accompanied by inhibition of the ligand-specific interaction of calreticulin with the respective integrins in the two cell types. Additionally, we found that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) resulted in prolongation of the calreticulin-integrin interaction, and enhancement of PC-3 cell attachment to collagen IV. We conclude that calreticulin interacts transiently with integrins during cell attachment and spreading. This interaction depends on receptor occupation, is ligand-specific, and can be modulated by protein phosphatase and MEK activity.

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Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion

Cited by 365 publications

References 27 publications

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

Ligand-specific, transient interaction between integrins and calreticulin during cell adhesion to extracellular matrix proteins is dependent upon phosphorylation/dephosphorylation events

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