Adaptors as central mediators of signal transduction in immune cells

Jordan, Martha S.; Singer, Andrew L.; Koretzky, Gary A.

doi:10.1038/ni0203-110

Cited by 245 publications

(224 citation statements)

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Among them, the adaptor molecule linker for activation of T cells (LAT) 4 plays a crucial role in that it coordinates the assembly of signaling complexes through multiple tyrosine residues within its intracytoplasmic segment. Most of the signaling activity of LAT appears funneled through the four C-terminal tyrosine residues found at positions 136, 175, 195, and 235 (1). Upon TCR-induced phosphorylation, these tyrosines show some specificity in the cytoplasmic proteins they recruit.…”

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confidence: 99%

“…Section 1734 solely to indicate this fact. 1 This work has been supported by institutional grants from Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique and a specific grant from the European Community (MUGEN Network of Excellence). I.P.…”

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confidence: 99%

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

Prinz

Grégoire

Mollenkopf

et al. 2005

The Journal of Immunology

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Linker for activation of T cells (LAT) is essential for T cell activation. Mice with mutations of distinct LAT tyrosine residues (LatY136F and Lat3YF) develop lymphoproliferative disorders involving TCR αβ or γδ T cells that trigger symptoms resembling allergic inflammation. We analyzed whether these T cells share a pattern of gene expression that may account for their pathogenic properties. Both LatY136F αβ and Lat3YF γδ T cells expressed high levels of the type 1 cysteinyl leukotriene receptor (CysLT1). Upon binding to the 5(S)-hydroxy-6(R)-S-cysteinylglycyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTD4) cysteinyl leukotriene, CysLT1 induced Ca2+ flux and caused chemotaxis in both LatY136F αβ and Lat3YF γδ T cells. Wild-type in vitro-activated T cells, but not resting T cells, also migrated toward LTD4 however with a lower magnitude than T cells freshly isolated from LatY136F and Lat3YF mice. These results suggest that CysLT1 is likely involved in the recruitment of activated αβ and γδ T cells to inflamed tissues.

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“…While p56lck can phosphorylate ITAMs, related src kinase p59fyn preferentially phosphorylates ADAP [6,7], and ZAP-70 targets linker for activation of T-cells (LAT) and 76-kDa src homology 2 domain-containing leukocyte phosphoprotein (SLP-76) [8,9]. From this work evolved the identification of so-called immune cell specific "adaptor proteins" or "molecular scaffolds" that possess discrete molecular domains or binding sites for the generation of complexes [10][11][12]. These complexes of proteins integrate TcR signals for downstream effecter functions such as cytokine production [11].…”

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confidence: 99%

T-cell signaling and immunopathologies

Rudd

2010

Semin Immunopathol

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Adaptors as central mediators of signal transduction in immune cells

Cited by 245 publications

References 89 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

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

T-cell signaling and immunopathologies

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