Specific Subdomains of Vav Differentially Affect T Cell and NK Cell Activation

Billadeau, Daniel D.; Mackie, Stacy M.; Schoon, Renée A.; Leibson, Paul J.

doi:10.4049/jimmunol.164.8.3971

Cited by 52 publications

(64 citation statements)

References 74 publications

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“…The proline-rich region deletion mutant has previously been shown to have only a minor defect in regulating transcription in T cells (22). The observed difference supports an earlier notion that intracellular mechanisms regulating NK cell-mediated cytotoxicity and transcription in T cells are not always overlapping (38). Alternatively, deletion of the entire proline-rich region may result in a conformation different from that of a protein with multiple proline to alanine point mutations.…”

Section: Discussionsupporting

confidence: 70%

Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Jevremović

Billadeau

Schoon

et al. 2001

The Journal of Immunology

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Stimulation of lymphocytes through multichain immune recognition receptors activates multiple signaling pathways. Adaptor proteins play an important role in integrating these pathways by their ability to simultaneously bind multiple signaling components. Recently, the 3BP2 adaptor protein has been shown to positively regulate the transcriptional activity of T cells. However, the mechanisms by which signaling components are involved in this regulation remain unclear, as does a potential role for 3BP2 in the regulation of other cellular functions. Here we describe a positive regulatory role for 3BP2 in NK cell-mediated cytotoxicity. We also identify p95vav and phospholipase C-γ isoforms as binding partners of 3BP2. Our results show that tyrosine-183 of 3BP2 is specifically involved in this interaction and that this residue critically influences 3BP2-dependent function. Therefore, 3BP2 regulates NK cell-mediated cytotoxicity by mobilizing key downstream signaling effectors.

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Section: Discussionsupporting

confidence: 70%

Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Jevremović

Billadeau

Schoon

et al. 2001

The Journal of Immunology

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“…Upon T-cell receptor stimulation, Vav1 is recruited to a signaling complex through a LAT-Gad-SLP76-Vav1 set of interactions (9,20). However, as LAT and SLP76 are dispensable for NK cytotoxicity (47,62), and as overexpression of a PH domaindeleted Vav1 still resulted in enhanced lysis of K562 cells by NK cells (6), what signals and what molecular interactions recruit Vav1 during NK cell activation are unclear. The early activation signal(s) in NK cells that leads to Vav1 phosphorylation may be delivered by specialized receptors or, alternatively, by the same activation receptors that induce cytotoxicity once signal amplification through Vav1-dependent receptor clustering has taken place.…”

Section: Discussionmentioning

confidence: 99%

Vav1 Dephosphorylation by the Tyrosine Phosphatase SHP-1 as a Mechanism for Inhibition of Cellular Cytotoxicity

Stebbins

Watzl

Billadeau

et al. 2003

Molecular and Cellular Biology

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243

237

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Here, we present data suggesting a novel mechanism for regulation of natural killer (NK) cell cytotoxicity through inhibitory receptors. Interaction of activation receptors with their ligands on target cells induces cytotoxicity by NK cells. This activation is under negative control by inhibitory receptors that recruit tyrosine phosphatase SHP-1 upon binding major histocompatibility class I on target cells. How SHP-1 blocks the activation pathway is not known. To identify SHP-1 substrates, an HLA-C-specific inhibitory receptor fused to a substrate-trapping mutant of SHP-1 was expressed in NK cells. Phosphorylated Vav1, a regulator of actin cytoskeleton, was the only protein detectably associated with the catalytic site of SHP-1 during NK cell contact with target cells expressing HLA-C. Vav1 trapping was independent of actin polymerization, suggesting that inhibition of cellular cytotoxicity occurs through an early dephosphorylation of Vav1 by SHP-1, which blocks actin-dependent activation signals. Such a mechanism explains how inhibitory receptors can block activating signals induced by different receptors.In many cell types, activation induced by cell contact is controlled by inhibitory receptors that bind ligands on target cells (41, 48). The importance of this type of negative regulation is illustrated by the protection of normal cells from lysis by NK cells, of red blood cells from ingestion by macrophages (44), and of cardiomyocytes from immunoglobulin G (IgG)-mediated autoimmunity (43). A common feature of the receptors involved in these protective functions (i.e., CD158, SIRP-␣, and PD-1, respectively) and of many other receptors that inhibit cellular responses is the presence of immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tail (12,48). Upon Tyr phosphorylation, ITIMs bind to the SH2 domains of protein tyrosine phosphatases (PTPases) SHP-1 and SHP-2, thereby releasing the catalytic site from autoinhibition (2, 12). Activation of human NK cell and T cell cytotoxicity is controlled by several inhibitory receptors, including the CD158 killer cell Ig-like receptors (KIR) and the lectin-like CD94/NKG2A, which bind to major histocompatibility complex (MHC) class I molecules expressed on target cells (5).Whereas the functional consequence of SHP-1 recruitment by ITIM-containing receptors in NK cells is well established, the specific point at which SHP-1 blocks activation signals has not been defined. Engagement of inhibitory receptors by ligands on target cells blocks conjugate formation (13), Ca 2ϩ flux (38, 52), polarization of lipid rafts in NK cells (42), and actin cytoskeleton rearrangement in T cells (26). As NK cell cytotoxicity depends on the activity of Tyr kinases (40), a number of Tyr-phosphorylated proteins are potential substrates for dephosphorylation by SHP-1. Two nonexclusive models, a "promiscuous" and a "selective" model, can be proposed for SHP-1-mediated inhibition. First, recruitment and activation of SHP-1 by inhibitory receptors at the NK-target cell interfac...

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“…However, this defect was not absolute, and TCR stimulation could still induce substantial Ca 2ϩ mobilization in the cells which apparently was sufficient for NFAT activation (23). In addition, vaccinia virus-driven Vav overexpression was recently found to increase the TCR-stimulated Ca 2ϩ response (4). Overall, these findings suggest that, although Vav has the potential to regulate Ca 2ϩ pathways in T cells, it is not absolutely essential, and that other TCR-associated Ca 2ϩ signaling pathways, which are independent of Vav, exist in T cells.…”

Section: Discussionmentioning

confidence: 99%

Vav-Rac1-Mediated Activation of the c-Jun N-Terminal Kinase/c-Jun/AP-1 Pathway Plays a Major Role in Stimulation of the Distal NFAT Site in the Interleukin-2 Gene Promoter

Kaminuma

Deckert

Elly

et al. 2001

Molecular and Cellular Biology

103

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The proto-oncogene product Vav, which is expressed specifically in hematopoietic and trophoblast cells, plays crucial roles in the development and activation of T cells triggered through the antigen-specific T-cell receptor (TCR) (7, 48). Vav enhances basal and TCR-activated transcription of the interleukin-2 (IL-2) gene, and this enhancement is largely mediated by activation of the distal NFAT element in the IL-2 gene promoter (NFAT-IL-2) (12, 24, 63). As in the case of other NFAT-binding sites (44), this element represents a binding site for a cooperative complex of the transcription factors NFAT and AP-1 (25, 40). This fact confounds an accurate assessment of the relative importance of NFAT versus AP-1 in NFAT-IL-2 activation, as measured by standard reporter assays. Consistent with the ability of Vav to upregulate the activity of NFAT, several studies demonstrated reduced Ca 2ϩ mobilization in T cells from Vav-deficient mice (9,16,17,23,60). However, this issue remains controversial in view of apparently contradictory findings that documented intact nuclear translocation and DNA-binding activities of NFAT (23) (10,42,59) suggests that Vav may also enhance AP-1 activation, since JNK is one of the upstream kinases involved in AP-1 activation via the phosphorylation of c-Jun (13,22,55). Consistent with this notion, we recently found that transient overexpression of Vav greatly increases AP-1 activity in T cells (61), although another recent study reported that Vav does not play a role in AP-1 activation (15).Here, we further analyzed the mechanism of Vav-mediated NFAT-IL-2 activation, with particular emphasis on the contribution of AP-1 and its potential importance as a Vav target in T cells. We also assessed the effects of Vav on the nuclear translocation and DNA-binding activities of NFAT proteins. Our findings indicate that Vav-induced activation of c-Jun/ AP-1, which depends on an intact Rac or JNK pathway, plays a major role in NFAT-IL-2 activation and, furthermore, that Vav may have a relatively minor role in direct NFAT activation.

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Specific Subdomains of Vav Differentially Affect T Cell and NK Cell Activation

Cited by 52 publications

References 74 publications

Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2

Vav1 Dephosphorylation by the Tyrosine Phosphatase SHP-1 as a Mechanism for Inhibition of Cellular Cytotoxicity

Vav-Rac1-Mediated Activation of the c-Jun N-Terminal Kinase/c-Jun/AP-1 Pathway Plays a Major Role in Stimulation of the Distal NFAT Site in the Interleukin-2 Gene Promoter

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