Modulation of TCR responsiveness by the Grb2-family adaptor, Gads

Lugassy, Jennie; Corso, Jasmin; Beach, Dvora; Petrik, Thomas; Oellerich, Thomas; Urlaub, Henning; Yablonski, Deborah

doi:10.1016/j.cellsig.2014.10.005

Cited by 14 publications

(35 citation statements)

References 50 publications

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“…8). The latter pathway may explain the observation that SLP-76 phosphorylation is not reduced in Gads-deficient Jurkat cells (Lugassy et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Lewis

Scangarello

Murphy

et al. 2018

Journal of Cell Science

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Antigen recognition by the T cell receptor (TCR) directs the assembly of essential signaling complexes known as SLP-76 (also known as LCP2) microclusters. Here, we show that the interaction of the adhesion and degranulation-promoting adaptor protein (ADAP; also known as FYB1) with SLP-76 enables the formation of persistent microclusters and the stabilization of T cell contacts, promotes integrin-independent adhesion and enables the upregulation of CD69. By analyzing point mutants and using a novel phosphospecific antibody, we show that Y595 is essential for normal ADAP function, that virtually all tyrosine phosphorylation of ADAP is restricted to a Y595-phosphorylated (pY595) pool, and that multivalent interactions between the SLP-76 SH2 domain and its binding sites in ADAP are required to sustain ADAP phosphorylation. Although pY595 ADAP enters SLP-76 microclusters, nonphosphorylated ADAP is enriched in protrusive actin-rich structures. The pre-positioning of ADAP at the contact sites generated by these structures favors the retention of nascent SLP-76 oligomers and their assembly into persistent microclusters. Although ADAP is frequently depicted as an effector of SLP-76, our findings reveal that ADAP acts upstream of SLP-76 to convert labile, Ca 2+-competent microclusters into stable adhesive junctions with enhanced signaling potential.

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“…8). The latter pathway may explain the observation that SLP-76 phosphorylation is not reduced in Gads-deficient Jurkat cells (Lugassy et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Lewis

Scangarello

Murphy

et al. 2018

Journal of Cell Science

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“…Gads-deficient cell line, dG32 [38] Gads Y45F Tyr 45 substituted with phenylalanine Gads ΔN (Δ2-53) N-terminal SH3 deleted Gads F92D [42] SH2 dimerization interface disrupted (disrupts binding to LAT) Gads F92A,R109A [42] Gads P321L [53] Disrupts binding of Gads C-SH3 to SLP-76 RXXK motif SLP-76-deficient cell line, J14 [54] SLP…”

Section: Parental Cell Line Reconstituted With Descriptionmentioning

confidence: 99%

“…Itk-mediated phosphorylation of PLC-γ1 is facilitated by Gads [38,39], a Grb2-family adaptor that bridges the TCR-inducible recruitment of SLP-76 to phospho-LAT [ Figure 1A, center, reviewed in 3]. Composed of a central SH2 domain, flanked by two SH3 domains and a unique linker region, Gads binds constitutively to SLP-76, via a high affinity interaction of its C-terminal SH3 domain with a conserved RxxK motif on SLP-76 [33,40,41].…”

Section: Introductionmentioning

confidence: 99%

“…Gads bridging activity supports PLC-γ1 phosphorylation, by bringing SLP-76-bound Itk (Figure 1 Once formed, the LAT-nucleated signaling complex may be regulated by post-translational events occurring within the complex. HPK1, a SLP-76-associated Ser/Thr kinase, can negatively p4 regulate TCR signaling by phosphorylating SLP-76 at S376 [43,44], and by phosphorylating Gads at T262 [38,45]. Conversely, SLP-76-associated Itk promotes TCR responsiveness by phosphorylating SLP-76 at Y173 [21].…”

Section: Introductionmentioning

confidence: 99%

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Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Hallumi

Shalah

Lo³

et al. 2020

Preprint

Self Cite

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The costimulatory receptor, CD28, synergizes with the T cell antigen receptor (TCR) to promote IL-2 production, cell survival and proliferation. Despite their profound synergy, the obligatory interdependence of the signaling pathways initiated by these two receptors is not well understood. Upon TCR stimulation, Gads, a Grb2-family adaptor, bridges the interaction of two additional adaptors, LAT and SLP-76, to form a TCR-induced effector signaling complex. SLP-76 binds the Tec-family tyrosine kinase, Itk, which phosphorylates SLP-76 at Y173 and PLC-γ1 at Y783. Here we identified Gads Y45 as an additional TCR-inducible, Itk-mediated phosphorylation site. Y45 is found within the N-terminal SH3 domain of Gads, an evolutionarily conserved domain with no known binding partners or signaling function. Gads Y45 phosphorylation depended on the interaction of Gads with SLP-76 and on the preferentially-paired binding of Gads to phospho-LAT. Three Itk-related features, Gads Y45, SLP-76 Y173, and a proline-rich Itk SH3-binding motif on SLP-76, were selectively required for activation of the CD28 RE/AP transcriptional element from the IL-2 promoter, but were not required to activate NFAT. This study illuminates a new regulatory module, in which Itk-targeted phosphorylation sites on two adaptor proteins, SLP-76 and Gads, control the transcriptional response to TCR/CD28 costimulation, thus enforcing the obligatory interdependence of the TCR and CD28 signaling pathways.

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“…During the process of negative selection some thymocytes destined for failure have an opportunity for redemption, utilizing a process called TCR editing . Rather than a single attempt at TCR generation, which was the prevailing paradigm for many years, self‐reactive thymocytes can be induced to re‐express the RAG proteins, which will once again rearrange TCR genes .…”

Section: Generation Of Rogue T Cells and Central Tolerancementioning

confidence: 99%

Of the multiple mechanisms leading to type 1 diabetes, T cell receptor revision may play a prominent role (is type 1 diabetes more than a single disease?)

Wagner

2016

Clinical and Experimental Immunology

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Summary A single determinant factor for autoimmunity does not exist; disease development probably involves contributions from genetics, the environment and immune dysfunction. Type 1 diabetes is no exception. Genomewide‐associated studies (GWAS) analysis in T1D has proved disappointing in revealing contributors to disease prediction; the only reliable marker has been human leucocyte antigen (HLA). Specific HLAs include DR3/DR4/DQ2/DQ8, for example. Because HLA molecules present antigen to T cells, it is reasonable that certain HLA molecules have a higher affinity to present self‐antigen. Recent studies have shown that additional polymorphisms in HLA that are restricted to autoimmune conditions are further contributory. A caveat is that not all individuals with the appropriate ‘pro‐autoimmune’ HLA develop an autoimmune disease. Another crucial component is autoaggressive T cells. Finding a biomarker to discriminate autoaggressive T cells has been elusive. However, a subset of CD4 helper cells that express the CD40 receptor have been described as becoming pathogenic. An interesting function of CD40 on T cells is to induce the recombination‐activating gene (RAG)1/RAG2 T cell receptor recombination machinery. This observation is contrary to immunology paradigms that changes in TCR molecules cannot take place outside the thymic microenvironment. Alteration in TCR, called TCR revision, not only occurs, but may help to account for the development of autoaggressive T cells. Another interesting facet is that type 1 diabetes (T1D) may be more than a single disease; that is, multiple cellular components contribute uniquely, but result ultimately in the same clinical outcome, T1D. This review considers the process of T cell maturation and how that could favor auto‐aggressive T cell development in T1D. The potential contribution of TCR revision to autoimmunity is also considered.

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Modulation of TCR responsiveness by the Grb2-family adaptor, Gads

Cited by 14 publications

References 50 publications

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Of the multiple mechanisms leading to type 1 diabetes, T cell receptor revision may play a prominent role (is type 1 diabetes more than a single disease?)

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