Positive Regulation of T Cell Activation and Integrin Adhesion by the Adapter Fyb/Slap

Griffiths, Emily K.; Krawczyk, Connie M.; Kong, Young‐Yun; Raab, Monika; Hyduk, Sharon J.; Bouchard, Denis; Chan, Vivien; Kozieradzki, I.; Oliveira-dos-Santos, Antonio J.; Wakeham, Andrew; Ohashi, Pamela S.; Cybulsky, Myron I.; Rudd, Christopher E.; Penninger, Josef

doi:10.1126/science.1063397

Cited by 264 publications

(305 citation statements)

References 25 publications

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“…To date, a role for SLP-76 in integrin activation has been limited to its association with ADAP, inasmuch as prevention of SLP-76/ADAP binding inhibits conjugate formation, which has been shown to be an integrin-mediated event [33]. ADAP itself has been directly linked to integrin activation, as ADAP -/-T cells do not adhere to fibronectin, ICAM, or VCAM following TCR ligation [31,32]. One model for how a SLP-76/ ADAP association may lead to integrin activation is through Src kinase-associated phosphoprotein of 55 kDa, an adaptor that is constitutively associated with ADAP [52] and has been linked to TCR-induced integrin activation [53,54].…”

Section: Discussionmentioning

confidence: 99%

“…Its exact role and the molecular mechanism for SLP-76-dependent integrin activation, however, are unclear. Recent data have shown that ADAP, a protein known to be involved in integrin activation [31,32], requires association with SLP-76 via the SLP-76 SH2 domain to mediate enhanced integrin-dependent T cell/ APC conjugate formation and adhesion to ICAM-1 (a b2 ligand) upon overexpression in Jurkat cells [31]. Complementing this finding, overexpression of the SH2 domain of SLP-76 blocks conjugate formation [33].…”

Section: Introductionmentioning

confidence: 87%

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In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

Jordan¹,

Kliche²,

Shabason³

et al. 2007

Eur J Immunol

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Multi-molecular complexes nucleated by adaptor proteins play a central role in signal transduction. In T cells, one central axis consists of the assembly of several signaling proteins linked together by the adaptors linker of activated T cells (LAT), Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads). Each of these adaptors has been shown to be important for normal T cell development, and their proper sub-cellular localization is critical for optimal function in cell lines. We previously demonstrated in Jurkat T cells and a rat basophilic leukemic cell line that expression of a 50-amino acid polypeptide identical to the site on SLP-76 that binds to Gads blocks proper localization of SLP-76 and SLP-76-dependent signaling events. Here we extend these studies to investigate the ability of this polypeptide to inhibit TCR-induced integrin activity in Jurkat cells and to inhibit in vivo thymocyte development and primary T cell function. These data provide evidence for the in vivo function of a dominant-negative peptide based upon the biology of SLP-76 action and suggest the possibility of therapeutic potential of targeting the SLP-76/Gads interaction. IntroductionStimulation of T cells through the T cell receptor (TCR) leads to recruitment and localization of several critical signaling proteins, which results in the generation of a macro-molecular signaling complex. Key components of this complex, or signalosome, include the adaptors Src homology 2 (SH2) domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads), which serves to link SLP-76 and its associated molecules to the transmembrane adaptor linker of activated T cells (LAT) [1].As an adaptor protein, SLP-76 possesses no enzymatic activity but functions via interaction with multiple proteins by way of three structural domains [2][3][4]. The N terminus harbors three tyrosines that become phos- phorylated upon TCR engagement [5,6] and have been reported to serve as docking sites for the guanine nucleotide exchange factor Vav, the adaptor protein Nck, the Tec family kinase Itk, and the p85 subunit of PI3K [7][8][9][10][11][12][13][14][15][16]. A single SH2 domain resides in the C-terminal portion of SLP-76 and links it to the adhesion and degranulation-promoting adaptor protein (ADAP) and to the hematopoietic progenitor kinase 1 [17][18][19]. Hematopoietic progenitor kinase 1, in turn, has been shown to phosphorylate SLP-76, creating a binding site for 14-3-3, a negative regulator of TCR signaling [20,21]. The central proline-rich region binds phospholipase Cc- Targeted deletion of SLP-76 in mice results in an inability of thymocytes to progress past the CD4 -CD8 -double-negative (DN) stage of development and thus a complete absence of mature T cells [28,29]. Since T cells do not develop in the absence of SLP-76, much of our knowledge of the role of SLP-76 in mature TCR signaling has been derived from the study of J14 ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

Jordan¹,

Kliche²,

Shabason³

et al. 2007

Eur J Immunol

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“…(a) interferon-inducible proteins (eg allograft inflammatory factor-1, interferon-induced 15 kDa protein 42 ); (b) signal transduction pathways (eg nuclear factor kappa B (NF-kB) modulator, NF-kB-inducing kinase, src-like adaptor protein (SLAP), 43 nck, 44 Among the above mentioned genes, we focused on TIA-1, a gene encoding a 15 kDa cytotoxic granuleassociated protein whose expression is restricted to CTL and NK cells. 49 This RNA-binding protein, lately renamed GMP-17 (granule membrane protein-17), 50 is considered a candidate effector of apoptotic cell death because of its ability to trigger DNA fragmentation of target cells.…”

Section: Il-10 and Nk Cell Activation/cytotoxicitymentioning

confidence: 99%

IL-10 stimulatory effects on human NK cells explored by gene profile analysis

et al. 2004

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The molecular mechanisms underlying the increase of natural killer (NK) cell anticancer activity mediated by interleukin (IL)-10 have not been elucidated. The aim of this study was to identify potential molecular mediators of IL-10 stimulatory effects by exploring the NK cell gene display induced by this cytokine. Gene profile was determined by high-throughput cDNA microarray and quantitative real-time PCR. In vitro, NK cells resting or conditioned with IL-10 were tested for cytotoxicity, migration and proliferation. IL-10 enhanced mRNA levels of cell activation/cytotoxicity-related genes (eg secretogranin, TIA-1, HMG-1, interferon-inducible genes) not upregulated by IL-2. In line with these findings, IL-10 increased NK cell in vitro cytotoxicity against Daudi cells. Unlike IL-2, IL-10 did not show any significant effect on NK cell in vitro proliferation and migration. However, gene profile analysis showed that IL-10 increased the expression of cell migration-related genes (eg L-selectin, vascular endothelium growth factor receptor-1, plasminogen activator, tissue; formyl peptide receptor, lipoxin A4 receptor), which might support a stimulatory effect not evident with the in vitro functional assay. Overall, gene profiling allowed us to formulate new hypotheses regarding the molecular pathways underlying the stimulatory effects of IL-10 on NK cells, supporting further investigation aimed at defining its role in cancer immune rejection.

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“…Le même type de relation semble s'établir entre les récepteurs de la glycine et la géphyrine [36]. [40,41]. Cette fonction pourrait également être assurée indirectement par des composants du complexe de signalisation déjà décrits.…”

Section: Regroupement De Récepteurs Et Adaptateurs Spécifiquesunclassified

Synapses immunologiques et synapses neuronales

et al. 2003

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Le mot synapse, créé par Sherrington en 1897 à partir du mot grec συναπòιò qui signifie liaison, action de joindre, a pendant un siècle été utilisé exclusivement en neurobiologie pour désigner la zone d'interaction et de communication entre neurones, ou entre neurones et cellules musculaires. Le terme de « synapse immunologique » est apparu récemment [1]. Il désigne la zone de contact entre une cellule du système immunitaire à vocation effectrice (lymphocyte T ou B, cellule natural killer) et une cellule présentant l'antigène (antigen presenting cell ou APC) qui peut être une cellule B, un macrophage, une cellule dendritique (dendritic cell ou DC) ou toute cellule cible ayant à sa surface des déterminants antigé-niques reconnus spécifiquement par la cellule effectrice. Il n'existe pas « une » synapse immunologique unique et canonique, mais « des » synapses immunologiques distinctes, compte tenu des caractéristiques moléculaires des différents acteurs cellulaires mis en jeu, et des diffé-rentes fonctions assurées: détecter la présence d'un antigène à la surface d'une APC, pour une cellule T naïve, pour être « activée » et proliférer; détecter la présence d'un antigène à la surface d'une cible et la tuer, pour une cellule T CD8 activée; délivrer des cytokines localement à une cellule B pour provoquer sa différencia-tion, dans le cas d'une cellule T CD4 activée, etc. La synapse immunologique la plus étu-diée est celle formée par une cellule T et une APC [2][3][4]. L'objet de cet article est d'examiner ces synapses T en utilisant comme élément de comparaison les synapses du système nerveux (synapses N). Caractéristiques de la synapse TLa structure moléculaire détectée par un lymphocyte T sur une APC n'est jamais un antigène soluble mais est constituée par l'association d'un peptide antigénique (du moins dans le cas des cellules Tαβ) avec une molécule du complexe majeur d'histocompatibilité (CMH) de classe I ou de classe II. Dans cette reconnaissance, le récepteur de l'antigène (T cell receptor ou TCR) joue un rôle essentiel comme support de la spécificité, mais il fonctionne au sein d'un important complexe multimoléculaire « synaptique », différent selon les systèmes expérimentaux considérés. MEDECINE/SCIENCES 2003 ; 19 : 429-36 REVUES SYNTHÈSE > Les systèmes nerveux et immunitaire ont en commun de constituer dans l'organisme des réseaux complexes de cellules en interaction. Dans ces réseaux transitent en permanence d'énormes quantités d'informations, codées de façon très différente dans les deux cas. Ces informations doivent en particulier circuler de cellule en cellule. Dans le système nerveux, ce transfert a lieu au niveau des synapses. Récemment, les immunologistes ont adopté le terme de synapse immunologique pour désigner l'interface entre deux cellules du système immunitaire. Mais est-il légitime d'appeler cette structure synapse? Peut-on y mettre en évidence un mode d'organisation ou de fonctionnement en rapport avec ceux des synapses nerveuses? <

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Positive Regulation of T Cell Activation and Integrin Adhesion by the Adapter Fyb/Slap

Cited by 264 publications

References 25 publications

In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

IL-10 stimulatory effects on human NK cells explored by gene profile analysis

Synapses immunologiques et synapses neuronales

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