Tailoring T-cell receptor signals by proximal negative feedback mechanisms

Acuto, Oreste; Bartolo, Vincenzo Di; Michel, Frédérique

doi:10.1038/nri2397

Cited by 227 publications

(290 citation statements)

References 110 publications

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“…Central mediators of T-cell adhesion are integrins as, for example, the aLb2 integrin leukocyte function-associated antigen-1 (LFA-1), whose activation is mediated by chemokines or antigen receptor encounter and the b1 family of integrins (very late antigen; a4b1, a5b1 and a6b1). LFA-1 activation after TCR stimulation, also referred to as inside-out signaling, relies on a signaling module composed of the transmembranous adapter LAT (linker for activation of T cells) and the cytosolic adaptors SLP-76 (76-kDa src homology 2 domain-containing leukocyte phosphoprotein) and Gads (Grb2-related adaptor downstream of Shc) [1,2]. Two additional adapter molecules, adhesion and degranulation promoting adaptor protein (ADAP) and 55-kDa src kinase associated phosphoprotein (SKAP-55), are recruited upon TCR-mediated phosphorylation of ADAP on Y 595 DDV or Y 651 DDV to the SH2-domain of SLP-76 [3,4].…”

Section: Introductionmentioning

confidence: 99%

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

et al. 2010

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The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFjB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.Key words: ADAP . HPK1 . LFA-1 . Rap1 . SLP-76Supporting Information available online Introduction T-cell adhesion to other immune cells or endothelium is crucial in generating an immune response. Central mediators of T-cell adhesion are integrins as, for example, the aLb2 integrin leukocyte function-associated antigen-1 (LFA-1), whose activation is mediated by chemokines or antigen receptor encounter and the b1 family of integrins (very late antigen; a4b1, a5b1 and a6b1). LFA-1 activation after TCR stimulation, also referred to as inside-out signaling, relies on a signaling module composed of the transmembranous adapter LAT (linker for activation of T cells) and the cytosolic adaptors SLP-76 (76-kDa src homology 2 domain-containing leukocyte phosphoprotein) and Gads (Grb2-related adaptor downstream of Shc) [1,2]. Two additional adapter molecules, adhesion and degranulation promoting adaptor protein (ADAP) and 55-kDa src kinase associated phosphoprotein 3220ing adapter molecule) which binds active Rap1 and thereby facilitates TCR-mediated integrin activation [5,6]. In addition, the Rap1-GTP effector regulator for cell adhesion and polarization enriched in lymphoid tissues (RapL) was recently shown to directly bind SKAP-55, which might differentially influence integrin affinity/avidity regulation [7]. Additional effectors of active Rap1 involved in integrin activation include the kinase Mst1 downstream of RapL and the serine/threonine kinase PKD1 [8][9][10].The hematopoietic progenitor kinase 1 (HPK1), a Ste20-homologous serine/threonine kinase, is activated upon TCR stimulation and feeds into MAPK and NFkB signaling [11][12][13][14]. Following recruitment to the TCR, HPK1 is pho...

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Section: Introductionmentioning

confidence: 99%

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

et al. 2010

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“…Similar to many other cell signaling pathways, the regulation of T cell activation is mediated largely through the regulation of protein posttranslational modifications. For instance, upon TCR ligation, lymphocyte-specific protein tyrosine kinase (LCK) phosphorylates the cytoplasmic tails of CD3, leading to the recruitment of ZAP-70, which potentiates the signaling cascade through phosphorylation of additional downstream substrates (1,2). Eventually, these early signaling events translate into the expression of new genes that are necessary for T cell effector function.…”

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Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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“…Consequently, the kinase ZAP70 is recruited and activated (12), thereby phosphorylating the downstream adaptor molecules LAT and SLP76. This initiates multiple downstream pathways essential for T cell activation (13). It was suggested that Erk is activated by recruitment of the Grb2-SOS complex to the phosphorylated TCR via the adaptor protein Shc (14).…”

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confidence: 99%

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D–interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220–TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

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Tailoring T-cell receptor signals by proximal negative feedback mechanisms

Cited by 227 publications

References 110 publications

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

HPK1 competes with ADAP for SLP‐76 binding and via Rap1 negatively affects T‐cell adhesion

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

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