TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization

Wallis, Alicia M.; Bishop, Gail A.

doi:10.1002/jlb.2mir0817-339rr

Cited by 14 publications

(19 citation statements)

References 50 publications

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“…TRAF1 to 6 were first identified as TNF-Receptor (TNFR) binding proteins, but it soon become evident that different members of the TRAF family were also involved in the regulation of pattern recognition receptors, including members of the Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and retinoic acid-inducible gene (RIG)-1-like Receptors (RLRs), thus demonstrating the key role of TRAF family proteins in the regulation of both innate and adaptive immunity [Reviewed by ( 6 )]. Moreover, some members of the TRAF family also regulate cytokine receptors ( 6 , 7 ). A role for TRAF family members in development has also been described ( 8 – 10 ).…”

Section: Brief Introduction To the Traf Protein Familymentioning

confidence: 99%

CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs

et al. 2018

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CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.

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Section: Brief Introduction To the Traf Protein Familymentioning

confidence: 99%

CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs

et al. 2018

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“…TRAF3 is also essential to promote T-cell-mediated immune responses, evident from the impaired immunity of mice with a T cell conditional Traf3 deficiency ( 38 ). We previously showed TRAF3 is required for enhancing early TCR signaling, which primes many other T cell effector functions ( 38 , 39 , 40 ). TRAF3 also regulates the differentiation and function of Treg ( 41 ) by recruiting the phosphatase PTPN2 to the IL-2 receptor.…”

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confidence: 99%

Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR

Hostager

Arkee

et al. 2021

Journal of Biological Chemistry

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Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) plays context-specific roles in multiple receptor-mediated signaling pathways in different cell types. Mice lacking TRAF3 in T cells display defective T-cell-mediated immune responses to immunization and infection and demonstrate defective early signaling via the TCR complex. However, the role of TRAF3 in the function of GITR/TNFRSF18, an important costimulatory member of the TNFR superfamily, is unclear. Here we investigated the impact of T cell TRAF3 status on both GITR expression and activation of specific kinases in the GITR signaling pathway in T cells. Our results indicate that TRAF3 negatively regulates GITR functions in several ways. First, expression of GITR protein was elevated in TRAF3-deficient T cells, resulting from both transcriptional and posttranslational regulation that led to greater GITR transcript levels, as well as enhanced GITR protein stability. TRAF3 associated with T cell GITR in a manner dependent upon GITR ligation. TRAF3 also inhibited several events of the GITR mediated early signaling cascade, in a manner independent of recruitment of phosphatases, a mechanism by which TRAF3 inhibits signaling through several other cytokine receptors. These results add new information to our understanding of GITR signaling and function in T cells, which is relevant to the potential use of GITR to enhance immune therapies.

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“…In unstimulated T cells, PAG is a transmembrane protein that localizes to lipid rafts and is usually in a phosphorylated state (the state required for binding to Csk). Upon T cell activation, PAG is dephosphorylated, leading to the release of Csk from the plasma membrane and distance from its potential substrates [200,201,202,203,204].…”

Section: Kinases and Phosphatases That Negatively Regulate T Cellsmentioning

confidence: 99%

Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity

Sitaram

Uyemura

Malarkannan

et al. 2019

IJMS

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It is well established that extracellular proteins that negatively regulate T cell function, such as Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), can be effectively targeted to enhance cancer immunotherapies and Chimeric Antigen Receptor T cells (CAR-T cells). Intracellular proteins that inhibit T cell receptor (TCR) signal transduction, though less well studied, are also potentially useful therapeutic targets to enhance T cell activity against tumor. Four major classes of enzymes that attenuate TCR signaling include E3 ubiquitin kinases such as the Casitas B-lineage lymphoma proteins (Cbl-b and c-Cbl), and Itchy (Itch), inhibitory tyrosine phosphatases, such as Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), inhibitory protein kinases, such as C-terminal Src kinase (Csk), and inhibitory lipid kinases such as Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase (SHIP) and Diacylglycerol kinases (DGKs). This review describes the mechanism of action of eighteen intracellular inhibitory regulatory proteins in T cells within these four classes, and assesses their potential value as clinical targets to enhance the anti-tumor activity of endogenous T cells and CAR-T cells.

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TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization

Cited by 14 publications

References 50 publications

CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs

CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs

Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR

Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity

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