Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation

Lasserre, Rémi; Cuche, Céline; Blecher‐Gonen, Ronnie; Libman, Evgeny; Biquand, Élise; Danckært, Anne; Yablonski, Deborah; Alcover, Andrés; Bartolo, Vincenzo Di

doi:10.1083/jcb.201103105

Cited by 59 publications

(49 citation statements)

References 39 publications

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“…Further investigation will be required to test this model. In addition to its expression level, Gads availability for signaling may be regulated by post-translational modifications, such as caspasemediated cleavage [49,50] or its phosphorylation at T262 [39]. Both mechanisms have been suggested to promote the release of SLP-76 from the LAT nucleated complex.…”

Section: Discussionmentioning

confidence: 97%

“…Functional assessment of this site was previously performed by overexpression of murine Gads T254A, in the presence of endogenous wild-type Gads [39]. The Gadsdeficient cell lines described here provided an opportunity to study this site in a cleaner genetic background.…”

Section: Modulation Of Gads Activity By Its Tonic Phosphorylation At mentioning

confidence: 99%

“…Human Gads T262 corresponds to murine Gads T254, a proposed negative regulatory site that may promote detachment of Gads from the LAT-nucleated signaling complex [39]. Functional assessment of this site was previously performed by overexpression of murine Gads T254A, in the presence of endogenous wild-type Gads [39].…”

Section: Modulation Of Gads Activity By Its Tonic Phosphorylation At mentioning

confidence: 99%

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

Lugassy

Corso

Beach

et al. 2015

Cellular Signalling

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Section: Discussionmentioning

confidence: 97%

Section: Modulation Of Gads Activity By Its Tonic Phosphorylation At mentioning

confidence: 99%

Section: Modulation Of Gads Activity By Its Tonic Phosphorylation At mentioning

confidence: 99%

See 1 more Smart Citation

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

Lugassy

Corso

Beach

et al. 2015

Cellular Signalling

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“…Insoluble material was removed by centrifugation at 20,800xg for 10 min at 4°C. Samples were either stored at –20°C or directly fractionated by electrophoresis on Novex NuPage gels (Life Technologies) using MOPS buffer, then transferred to nitrocellulose membranes and analyzed by immunoblotting, as described [13, 16]. …”

Section: Methodsmentioning

confidence: 99%

“…We previously identified a negative feedback loop downregulating TCR signaling and T cell activation, that involves Ser/Thr phosphorylation of SLP76 and GADS by the Hematopoietic Progenitor Kinase (HPK)1 [13, 16], a member of the Germinal Center Kinase family. We have shown that when HPK1 is recruited in early signaling complexes, through its binding to the SLP76 SH2 domain [17], it induces the phosphorylation of Ser376 in SLP76 and Thr262 in GADS.…”

Section: Introductionmentioning

confidence: 99%

Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function

et al. 2017

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The adapter protein SLP76 is a key orchestrator of T cell receptor (TCR) signal transduction. We previously identified a negative feedback loop that modulates T cell activation, involving phosphorylation of Ser376 of SLP76 by the hematopoietic progenitor kinase 1 (HPK1). However, the physiological relevance of this regulatory mechanism was still unknown. To address this question, we generated a SLP76-S376A-expressing knock-in mouse strain and investigated the effects of Ser376 mutation on T cell development and function. We report here that SLP76-S376A-expressing mice exhibit normal thymocyte development and no detectable phenotypic alterations in mature T cell subsets or other lymphoid and myeloid cell lineages. Biochemical analyses revealed that mutant T cells were hypersensitive to TCR stimulation. Indeed, phosphorylation of several signaling proteins, including SLP76 itself, phospholipase Cγ1 and the protein kinases AKT and ERK1/2, was increased. These modifications correlated with increased Th1-type and decreased Th2-type cytokine production by SLP76-S376A T cells, but did not result in significant changes of proliferative capacity nor activation-induced cell death susceptibility. Hence, our results reveal that SLP76-Ser376 phosphorylation does not mediate all HPK1-dependent regulatory effects in T cells but it fine-tunes helper T cell responses.

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The 14‐3‐3/SLP76 protein–protein interaction in T‐cell receptor signalling: a structural and biophysical characterization

et al. 2020

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The SH2 domain-containing protein of 76 kDa, SLP76, is an important adaptor protein that coordinates a complex protein network downstream of T-cell receptors (TCR), ultimately regulating the immune response. Upon phosphorylation on Ser376, SLP76 interacts with 14-3-3 adaptor proteins, which leads to its proteolytic degradation. This provides a negative feedback mechanism by which TCR signalling can be controlled. To gain insight into the 14-3-3/SLP76 protein-protein interaction (PPI), we have determined a high-resolution crystal structure of a SLP76 synthetic peptide containing Ser376 with 14-3-3r. We then characterized its binding to 14-3-3 proteins biophysically by means of fluorescence polarization and isothermal titration calorimetry. Furthermore, we generated two recombinant SLP76 protein constructs and characterized their binding to 14-3-3. Our work lays the foundation for drug design efforts aimed at targeting the 14-3-3/SLP76 interaction and, thereby, TCR signalling.

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Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation

Abstract: Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response.

Cited by 59 publications

References 39 publications

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

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

Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function

The 14‐3‐3/SLP76 protein–protein interaction in T‐cell receptor signalling: a structural and biophysical characterization

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