The Ubiquitin E3 Ligase Cbl-b in T Cells Tolerance and Tumor Immunity

Loeser, Stefanie; Penninger, Josef

doi:10.4161/cc.6.20.4797

Cited by 15 publications

(13 citation statements)

References 121 publications

(181 reference statements)

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“…One factor that regulates TCR signaling is c-CBL, a member of the C asitas B -lineage L ymphoma protein family and a ring-type E3 ubiquitin ligase that dampens TCR function by interacting with TCR-associated tyrosine kinases and promoting their degradation ( Schmidt and Dikic, 2005 ; Swaminathan and Tsygankov, 2006 ; Loeser et al, 2007 ; Paolino and Penninger, 2010 ; Qiao et al, 2013 ). The TCR is expressed on the cell surface in association with CD3 proteins to form the TCR/CD3 complex.…”

Section: Introductionmentioning

confidence: 99%

c-CBL E3 Ubiquitin Ligase Is Overexpressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation-Induced Cell Death

Salva

Wood

2015

Journal of Investigative Dermatology

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Mycosis fungoides (MF) and Sezary syndrome (SS) are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death (AICD) which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS-ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is over-expressed in CTCL and that its knockdown overcomes defective TCR signaling resulting in phosphorylation of PLCg1, calcium influx, ROS generation, up-regulation of FASL and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate (MTX) which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively.

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Section: Introductionmentioning

confidence: 99%

c-CBL E3 Ubiquitin Ligase Is Overexpressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation-Induced Cell Death

Salva

Wood

2015

Journal of Investigative Dermatology

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“…Cbl‐b was originally found in leukocyte subsets and identified as a negative regulator of T cell activation (Loeser and Penninger, ; Zhao et al, ). Our previous study demonstrated that Cbl‐b is also widely expressed in a variety of solid tumors, including gastric, breast, and lung cancer (Mu et al, ), and was closely associated with cell proliferation, survival, and invasiveness.…”

Section: Discussionmentioning

confidence: 99%

Suppressed expression of Cbl‐b by NF‐κB mediates icotinib resistance in EGFR‐mutant non‐small‐cell lung cancer

Zhang

Zheng

Hou

et al. 2019

Cell Biology International

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Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) could greatly improve the prognosis of NSCLC patients harboring activating EGFR mutations, drug resistance still remains a major obstacle to successful treatment. Our previous study found that the EGFR-TKI icotinib could upregulate the expression of Casitas-B-lineage lymphoma protein-B (Cbl-b), an E3 ubiquitin ligase. In the present study, we aimed to clarify the potential role of Cbl-b in the resistance to icotinib, and the underlying mechanisms using EGFR-mutant cell lines. We found that icotinib inhibited the proliferation of mutant-EGFR NSCLC cells (PC9 and HCC827), and upregulated the expression of Cbl-b at both the protein and mRNA levels. Cbl-b knockdown decreased the sensitivity of PC9 and HCC827 cells to icotinib, and partially restored icotinib-inhibited AKT activation in PC9 cells. On the contrary, Cbl-b overexpression could partly reverse the drug resistance in PC9 icotinib-resistant cells (PC9/IcoR). Moreover, overexpressing p65, the main member of transcription factor NF-κB family, reversed the icotinib-mediated upregulation of Cbl-b. Collectively, these data suggest that icotinib could upregulate Cbl-b mediated by NF-κB inhibition, and Cbl-b contribute to the icotinib sensitivity in EGFR-mutant NSCLC cells. This study highlights that low expression of Cbl-b might be the key obstacles in the efficacy of icotinib therapy.

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“…This assumption is based on the observation that, in addition to render T cells independence on CD28 for activation, the Cbl‐b −/− mutation effectively attenuates PD1 and TGFβ receptor signaling in T cells . Altered characteristics of Cbl‐b −/− T cells in the aforementioned receptor signaling indeed markedly enhances anti‐tumor immunity as Cbl‐b −/− mice become resistant to various inoculated tumors as well as to several models of spontaneous tumors . Strikingly, adoptive transfer of Cbl‐b −/− CD8 + T cells is sufficient to reject established tumor, thus validating the concept of using Cbl‐b −/− T cells to treat the tumors.…”

Section: The Function Of Cbl and Cbl‐b In T Lineage Cellsmentioning

confidence: 99%

Regulation of immune system development and function by Cbl‐mediated ubiquitination

Li¹,

Gong

2019

Immunological Reviews

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Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.

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The Ubiquitin E3 Ligase Cbl-b in T Cells Tolerance and Tumor Immunity

Cited by 15 publications

References 121 publications

c-CBL E3 Ubiquitin Ligase Is Overexpressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation-Induced Cell Death

c-CBL E3 Ubiquitin Ligase Is Overexpressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation-Induced Cell Death

Suppressed expression of Cbl‐b by NF‐κB mediates icotinib resistance in EGFR‐mutant non‐small‐cell lung cancer

Regulation of immune system development and function by Cbl‐mediated ubiquitination

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