The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Liu, Chi-Chao; Leclair, Pascal; Yap, Shyong Quin; Lim, C. J.

doi:10.1128/mcb.00580-13

Cited by 30 publications

(33 citation statements)

References 57 publications

(77 reference statements)

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“…21, 23, 24 This interaction is dependent on the GFFKR peptide motif found at the juxtamembrane cytosolic tail of α -integrins; thus, we speculated that α -integrin function may modulate surface CRT presentation. To address this, we assessed surface CRT levels for cells plated on integrin substrates.…”

Section: Resultsmentioning

confidence: 98%

“…Previously, we showed that α 4 δ -expressing cells do not adhere to an α 4 β 1-specific substrate, yet exhibit increased α 4 δ binding to CRT in an adhesion-independent manner. 23 …”

Section: Resultsmentioning

confidence: 99%

“…20 Several studies, including ours, have shown that integrin-mediated adhesion promotes binding of CRT, likely from the relatively low abundant cytosolic pool, to α -integrin tails in a manner requiring the GFFKR motif. 21, 22, 23, 24 In this study, we investigated if α -integrin function may impact upon cell surface presentation of CRT using T-acute lymphoblastic leukemia (T-ALL) cells, which are amenable to cell adhesion studies and cytotoxic drug treatments to induce ICD. We present evidence suggesting that adhesion-mediated integrin–CRT interaction occurring in the cytosol constitute a mechanism reducing CRT translocation to the cell surface, which has implications in antitumor immunomodulatory activity.…”

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confidence: 99%

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α-Integrin expression and function modulates presentation of cell surface calreticulin

Leclair

Monajemi

et al. 2016

Cell Death Dis

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Calreticulin presentation on the cell surface is an important hallmark of immunogenic cell death (ICD), serving as the prophagocytic signal for macrophages. Cell adhesion is a physiologically relevant stimulus previously shown to increase calreticulin interaction with α-integrins via the juxtamembrane, cytosolic GFFKR motif. This study assessed whether integrin function can regulate surface calreticulin levels in ICD. We generated calreticulin-null T-lymphoblasts and confirmed the loss of surface calreticulin expression on cells treated with doxorubicin, an ICD inducer. Reconstituted expression with full-length calreticulin targeted to the endoplasmic reticulum (ER) successfully rescued doxorubicin-induced surface calreticulin. Reconstitution with a truncation mutant calreticulin targeted to the cytosol led to constitutively high surface calreticulin that was not further elevated by doxorubicin, suggesting calreticulin released from the stressed ER transits the cytosol before its translocation to the cell surface. When stimulated to engage integrin substrates, doxorubicin-treated wild-type T-lymphoblasts exhibited decreased surface calreticulin compared with cells under non-adherent conditions. The inhibitory effect on surface calreticulin was recapitulated for cells in suspension treated with a β1-integrin-activating antibody, 9EG7. Similarly, cells expressing a truncated α-integrin cytosolic tail, bearing only the juxtamembrane GFFKR calreticulin-binding motif, exhibited low surface calreticulin with doxorubicin treatment under non-adherent conditions. Using partial permeabilization techniques to distinguish between cytosolic and ER staining, we found that ICD inducers promoted the accumulation of cytosolic calreticulin with negligible change in total calreticulin, suggesting that integrin-mediated inhibition of surface calreticulin was due to reduced cytosolic to surface translocation. T-lymphoblasts co-treated with an ICD inducer and 9EG7 exhibited reduced phagocytosis by macrophages when compared with treatment with only ICD inducer. This study reveals a previously uncharacterized function of integrins as negative regulators of ICD by suppressing presentation of cell surface calreticulin.

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Section: Resultsmentioning

confidence: 98%

“…Previously, we showed that α 4 δ -expressing cells do not adhere to an α 4 β 1-specific substrate, yet exhibit increased α 4 δ binding to CRT in an adhesion-independent manner. 23 …”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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α-Integrin expression and function modulates presentation of cell surface calreticulin

Leclair

Monajemi

et al. 2016

Cell Death Dis

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“…High expression levels of CD49d were identified as an adverse risk factor in childhood ALL [69], thereby marking it as a potential therapeutic target. It has been shown that CD49d enhanced chemoresistance to doxorubicin in ALL cells [69] [70] and that adhesion of ALL cells to the bone marrow microenvironment is mediated by CD49d. Several mechanisms for how it may exert its chemoprotective effect have been described.…”

Section: Microenvironment -Leukemia Cells Crosstalk: Cell-cell Interamentioning

confidence: 99%

The role of microenvironment and immunity in drug response in leukemia

Bakker

Qattan

Mutti

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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“…11,12 Integrins, particularly α4β1 and αVβ3, which control trafficking to and lodging of HSCs in the BMME, are also crucial for the persistence of minimal residual disease. [13][14][15] The Berlin-Frankfurt-Munster ALL trial (ALL-REZ BFM 2002) revealed that high expression of α4β1 at first relapse was associated with a poor molecular response to therapy and significantly worse eventfree and overall survival. 16 Based on these and other reports, 17 a concept emerged suggesting that a subpopulation of LSCs are quiescent and exhibit relative drug resistance as a result of enhanced adhesive properties toward bone marrow stroma.…”

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confidence: 99%