SLP-76 Coordinates Nck-Dependent Wiskott-Aldrich Syndrome Protein Recruitment with Vav-1/Cdc42-Dependent Wiskott-Aldrich Syndrome Protein Activation at the T Cell-APC Contact Site

Zeng, Rong; Cannon, Judy L.; Abraham, Robert T.; Way, Michael; Billadeau, Daniel D.; Bubeck-Wardenberg, Julie; Burkhardt, Janis K.

doi:10.4049/jimmunol.171.3.1360

Cited by 156 publications

(153 citation statements)

References 73 publications

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“…Intriguingly, Vav2, a GEF for the Rho family of Ras-related GTPases, was down-regulated after chronic TNF treatment. Vav is important in T cell activation (23), is required for synapse formation, and is necessary for Ca 2ϩ flux and activation of extracellular signal-regulated kinase (ERK) (23)(24)(25)(26)(27). Holsinger et al (28) showed that vavϪ/Ϫ T cells were deficient in IL-2 production and proliferation, and the peak of Ca 2ϩ mobilization was reduced, although of normal duration.…”

Section: Discussionmentioning

confidence: 99%

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

Lee

Lih²,

Huang

et al. 2008

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

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TNF-␣ plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNF exposure has been shown to downmodulate T cell responses. In a mouse T cell hybridoma model, TNF attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNF and anti-TNF exposure suppressed and increased T cell responses, respectively. In adult TCR (BDC2.5) transgenic nonobese diabetic mice, DNA microarray analysis of global gene expression in BDC2.5 CD4 ؉ T cells in response to chronic TNF or anti-TNF exposure showed that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible Src homology 2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin-1, -2, and -3) and calcium channel voltage-dependent, N type ␣1B subunit (CaV2.2) were induced by TNF, whereas Vav2, Rho GTPase-activating protein, calcium channel voltage-dependent, L type ␣1C subunit (CaV1.2), IL-1 receptor-associated kinase-1 and -2, and IL enhancer binding factor 3 were reduced by TNF. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNF, were induced by anti-TNF treatment. Further, we showed that chronic TNF exposure impaired NF-B and adaptor protein 1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNF exposure and provide candidate target genes that may function to mediate TNF-induced T cell unresponsiveness.

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Section: Discussionmentioning

confidence: 99%

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

Lee

Lih²,

Huang

et al. 2008

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

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“…Vav recruits and activates Cdc42, which is necessary for WASp activation. Activated WASp interacts with the Arp2/3 complex to initiate actin polymerization and cytoskeletal changes (Zeng et al 2003).…”

Section: Molecules Recruited To Lat Via Slp-76 Promote T-cell Activationmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

150

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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“…Once recruited to the LIME complex, Vav becomes activated and catalyzes the exchange of GDP for GTP, to activate Rac1. Activated Rac1 mediates actin polymerization presumably through WASP-Arp2/3, which strengthens conjugation with the APC (Lee and Dominguez, 2010;Zeng et al, 2003). Previously, TCR stimulation-dependent actin polymerization was shown to be mediated by Vav recruitment to the membrane by a mechanism involving the LAT-Gads-SLP-76 complex (Tuosto et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

LIME Mediates Immunological Synapse Formation through Activation of VAV

Son

Park

Lee

et al. 2012

Molecules and Cells

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Lck Interacting Membrane protein (LIME) was previously characterized as a transmembrane adaptor protein mediating TCR-dependent T cell activation. Here, we show that LIME associates with Vav in response to TCR stimulation and is required for Vav guanine nucleotide exchange factor (GEF) activity for Rac1. Consistent with this finding, actin polymerization at the immunological synapse (IS) was markedly enhanced by overexpression of LIME, but was reduced by expression of a LIME shRNA. Moreover, TCR-mediated cell adhesion to ICAM-1, laminin, or fibronectin was downregulated by expression of LIME shRNA. In addition, in the IS, LIME but not LAT was found to localize at the peripheral-supramolecular activation cluster (p-SMAC) where the integrins were previously shown to be localized. Together, these results establish LIME as a transmembrane adaptor protein linking TCR stimulation to IS formation and integrin activation through activation of Vav.

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SLP-76 Coordinates Nck-Dependent Wiskott-Aldrich Syndrome Protein Recruitment with Vav-1/Cdc42-Dependent Wiskott-Aldrich Syndrome Protein Activation at the T Cell-APC Contact Site

Cited by 156 publications

References 73 publications

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

LIME Mediates Immunological Synapse Formation through Activation of VAV

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SLP-76 Coordinates Nck-Dependent Wiskott-Aldrich Syndrome Protein Recruitment with Vav-1/Cdc42-Dependent Wiskott-Aldrich Syndrome Protein Activation at the T Cell-APC Contact Site

Cited by 156 publications

References 73 publications

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4+T cells

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4+T cells

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

LIME Mediates Immunological Synapse Formation through Activation of VAV

Contact Info

Product

Resources

About

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells