T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

Qiao, Guilin; Li, Zhenping; Molinero, Luciana; Alegre, Maria Luisa; Ying, Haiyan; Sun, Zuoming; Penninger, Josef; Zhang, Jian

doi:10.1128/mcb.01505-07

Cited by 86 publications

(78 citation statements)

References 55 publications

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“…In naive T cells, initiation of T cell cycling can occur in the absence of IL-2 (33, 35, 53) but appears to require prolonged TCR/CD28 engagement and the downstream activation of PI3K/PKB, Akt, and mammalian target of rapamycin (36). Cbl-b antagonizes TCR-and CD28-dependent proximal signaling of PI3K/PKB, Akt, and NF-κB (18)(19)(20)54), and the enhanced proliferation of Cblb -/-T cells has been shown to be dependent on PI3K (19). Thus, Cbl-b deficiency may be amplifying the IL-2-independent proliferation pathway in effector T cells by prolonging TCR and CD28 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Cbl-b increases the threshold for naive T cell activation by regulating TCR and CD28 signaling, in part by inhibiting PKCθ-and PI3K/Akt-dependent pathways, respectively (16)(17)(18)(19)(20). Abrogating Cbl-b expression rescues IL-2 production and proliferation by naive CD28 -/-T cells (16,17), which has therapeutic implications, since CD28 expression is often lost on T cells that have differentiated to effector cells during repetitive stimulations in vitro.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Stromnes¹,

Blattman²,

Tan³

et al. 2010

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Stromnes¹,

Blattman²,

Tan³

et al. 2010

J. Clin. Invest.

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“…Mutation of Ser109 to Ala residue in CARMA1 impairs its biological function [72]. Once activated, CARMA1 recruits the IKK complex [60,61] and other signaling molecules (Table 1) [63,[67][68][69]73], including Bcl10 and its pre-associated partner MALT1 [60,61,74]. TCR-induced formation of the CARMA1-Bcl10-MALT1 complex is critical for IKK activation.…”

Section: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Blonska¹,

Lin²

2010

Cell Res

171

200

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The NF-κB family of transcription factors plays a crucial role in cell activation, survival and proliferation. Its aberrant activity results in cancer, immunodeficiency or autoimmune disorders. Over the past two decades, tremendous progress has been made in our understanding of the signals that regulate NF-κB activation, especially how scaffold proteins link different receptors to the NF-κB-activating complex, the IκB kinase complex. The growing number of these scaffolds underscores the complexity of the signaling networks in different cell types. In this review, we discuss the role of scaffold molecules in signaling cascades induced by stimulation of antigen receptors, G-protein-coupled receptors and C-type Lectin receptors, resulting in NF-κB activation. Especially, we focus on the family of Caspase recruitment domain (CARD)-containing proteins known as CARMA and their function in activation of NF-κB, as well as the link of these scaffolds to the development of various neoplastic diseases through regulation of NF-κB.

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Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tomentioning

confidence: 99%

“…[36]. This results in the inhibition of Akt and PKCy-mediated NFkB activation [37], and additionally, prevents Vav1-mediated cytoskeleton rearrangements required for receptor clustering and synapse formation [38]. Furthermore, Cbl-b has been reported to destabilize the immune synapse by interfering with the CrkL/C3G signaling pathway [39].…”

Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tomentioning

confidence: 99%

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

Self Cite

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

Cited by 86 publications

References 55 publications

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

E3 ubiquitin ligases in T‐cell tolerance

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