An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells

Zha, Yuanyuan; Gajewski, Thomas F.

doi:10.1016/j.cellimm.2007.07.006

Cited by 11 publications

(14 citation statements)

References 48 publications

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“…Recent studies have shown that the ubiquitin ligase c-Cbl is a negative regulator of the MAPK/ERK pathway. 23 Our data show that IFNα alone significantly reduced c-Cbl protein levels after 48 and 72 h (Fig. 5A), which coincided with the increased expression of p-ERK (Fig.…”

Section: Discussionsupporting

confidence: 55%

“…20 It not only plays an essential role in sequestering signaling molecules from lipid rafts but also negatively regulates tyrosine kinase-mediated growth factor receptor signaling through ubiquitination and degradation of numerous signaling proteins. [21][22][23] In CD4 + T lymphocytes, transduction with dominant negative c-Cbl increases anti-CD3/CD28-induced phosphorylation of ERK, suggesting that c-Cbl could negatively regulate ERK activity. 23 However, whether c-Cbl is involved in the synergistic effects of IFNα and TRAIL on apoptosis induction is unclear.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

“…[21][22][23] In CD4 + T lymphocytes, transduction with dominant negative c-Cbl increases anti-CD3/CD28-induced phosphorylation of ERK, suggesting that c-Cbl could negatively regulate ERK activity. 23 However, whether c-Cbl is involved in the synergistic effects of IFNα and TRAIL on apoptosis induction is unclear.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

See 2 more Smart Citations

Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway

Qu¹,

Zhao²,

Teng³

et al. 2011

Cancer Biology & Therapy

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Section: Discussionsupporting

confidence: 55%

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

See 1 more Smart Citation

Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway

Qu¹,

Zhao²,

Teng³

et al. 2011

Cancer Biology & Therapy

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“…For example, T cells transduced to express a dominant-negative form of Cbl-b or that are deficient for SHP-1 (SH2-containing protein tyrosine phosphatase-1) exhibit an augmented T cell response to antigen (Lorenz et al, 1996;Fawcett and Lorenz, 2005;Zha and Gajewski, 2007), and preliminary studies with T cells deficient for either of these molecules have suggested increased efficacy in vivo (our unpublished data).…”

Section: Methods For Increasing Aviditymentioning

confidence: 94%

T Cell Receptor Gene Therapy for Cancer

2009

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T cell-based adoptive immunotherapy has been shown to be a promising treatment for various types of cancer. However, adoptive T cell therapy currently requires the custom isolation and characterization of tumor-specific T cells from each patient-a process that can be not only difficult and time-consuming but also often fails to yield high-avidity T cells, which together have limited the broad application of this approach as a clinical treatment. Employing T cell receptor (TCR) gene therapy as a component of adoptive T cell therapy strategies can overcome many of these obstacles, allowing autologous T cells with a defined specificity to be generated in a much shorter time period. Initial studies using this approach have been hampered by a number of technical difficulties resulting in low TCR expression and acquisition of potentially problematic specificities due to mispairing of introduced TCR chains with endogenous TCR chains. The last several years have seen substantial progress in our understanding of the multiple facets of TCR gene therapy that will have to be properly orchestrated for this strategy to succeed. Here we outline the challenges of TCR gene therapy and the advances that have been made toward realizing the promise of this approach.

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“…The adoptive transfer of T cells appears to be a promising new treatment for various types of cancer (31,32) and several strategies to increase the functional avidity of the TCR that target the binding of antigen at the cell surface have been proposed (33)(34)(35)(36). An alternate approach would be to manipulate intracellular signaling pathways that normally act to attenuate T-cell signaling such as those mediated by Cbl-b and SHP-1 (37)(38)(39). The data presented here show that introduction of a LAT molecule resistant to ubiquitylation is another option by which to augment T-cell potency.…”

Section: Discussionmentioning

confidence: 99%

Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation

Balagopalan

Ashwell

Bernot

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Linker for activation of T cells (LAT) plays a central role in T-cell activation by nucleating signaling complexes that are critical for the propagation of T-cell signals from the plasma membrane to the cellular interior. The role of phosphorylation and palmitoylation in LAT function has been well studied, but not much is known about other strategies by which the cell modulates LAT activity. We have focused on LAT ubiquitylation and have mapped the sites on which LAT is ubiquitylated. To elucidate the biological role of this process, we substituted LAT lysines with arginines. This resulted in a dramatic decrease in overall LAT ubiquitylation. Ubiquitylationresistant mutants of LAT were internalized at rates comparable to wild-type LAT in a mechanism that required Cbl family proteins. However, these mutants displayed a defect in protein turnover rates. T-cell signaling was elevated in cells reconstituted with LAT mutants resistant to ubiquitylation, indicating that inhibition of LAT ubiquitylation enhances T-cell potency. These results support LAT ubiquitylation as a molecular checkpoint for attenuation of T-cell signaling.endocytosis | protein degradation | ubiquitin A ntigen activation of T cells leads to major cellular changes essential to the onset of a productive immune response. The earliest events occur upon T-cell antigen receptor (TCR) engagement and include activation of protein tyrosine kinases (PTKs) and phosphorylation of multiple protein substrates. One critical PTK substrate is the integral membrane adapter molecule linker for activation of T cells (LAT), which upon phosphorylation, serves as a nucleation site for the formation of protein complexes composed of itself, other adapter molecules, and essential signaling enzymes activated at this site (1). A large number of studies have revealed that LAT-based complexes catalyze critical TCR-mediated signaling reactions and lead to the induction of multiple downstream pathways that direct almost all TCRinitiated cellular responses (2).T-cell signaling must be tightly regulated, otherwise autoimmunity or a compromised immune response might ensue. Clearly, signal attenuation occurs at various stages during signal propagation. Proximally, the number and type of inhibitory coreceptors that are engaged on the T cell following TCR engagement greatly influence signal strength (3, 4). In addition, activation of the TCR also triggers mechanisms within the TCR signaling machinery that can decrease TCR-mediated signaling, including dephosphorylation of substrates by phosphatases, as well as phosphorylation on inhibitory residues by kinases (5). Finally, ubiquitylation and activationinduced endocytosis of proteins from the plasma membrane and subsequent degradation may eliminate activated signaling molecules (6, 7). Thus, tuning the excitation threshold of a T cell requires the coordinated regulation of multiple negative regulators.A growing body of evidence supports the concept that clustering of the TCR and downstream signaling proteins is associated with and is ...

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An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells

Cited by 11 publications

References 48 publications

Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway

Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway

T Cell Receptor Gene Therapy for Cancer

Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation

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