Internalization of human T lymphocyte receptors

Telerman, Adam; Amson, Robert; Romasco, Franco; Wybran, Joseph; Galand, Paul; Mosselmans, Roger

doi:10.1002/eji.1830170715

Cited by 67 publications

(45 citation statements)

References 32 publications

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“…Both of these receptors are endocytosed via clathrin coated pits (Beguinot et al, 1985;Shin et al, 1991;Pelchen-Matthews et al, 1993). Likewise the TCR is endocytosed via clathrin coated pits following incubation with anti-TCR monoclonal antibodies (Telerman et al, 1987;Boyer et al, 1991) and this is probably also the pathway of TCR entry following PKC activation as indicated by the present experiments in which cells were incubated in hypertonic medium.…”

Section: Discussionsupporting

confidence: 53%

“…PKC induced TCR down-regulation is probably mediated by endocytosis via clathrin coated pits Previous studies have demonstrated that TCR internalization induced by monoclonal anti-TCR antibodies is mediated via clathrin coated pits (Telerman et al, 1987;Boyer et al, 1991). However, the pathway of TCR entry following PKCmediated internalization has not been described.…”

Section: Jgn-wt Cellsmentioning

confidence: 99%

“…After TCR stimulation, activation signals are transmitted across the membrane (Abraham et al, 1992) and both TCR internalization and antigen unresponsiveness can be induced by specific anti-TCR antibodies (Reinherz et al, 1982;Telerman et al, 1987;Boyer et al, 1991), by supra-optimal doses of antigen Zanders et al, 1983) or by phorbol esters (Ando et al, 1985;Cantrell et al, 1985). This raises the interesting possibility that physiologically important regulation of T cell function may be mediated through control of the level of TCR expression at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

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CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor.

et al. 1994

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Several cell surface receptors including the T cell receptor (TCR) are phosphorylated and down-regulated following activation of protein kinase C (PKC). Among other substrates the activated PKC in T cells phosphorylates the CD3-y subunit of the TCR. To investigate the role of CD3'y phosphorylation in PKC-mediated TCR downregulation, point mutated CD3,y cDNA was transfected into the CD3'y-negative T cell line JGN and CD3'y transfectants were analysed. Phosphorylation at S126 but not S123 in the cytoplasmic tail of CD3-y was required for PKC-mediated down-regulation of the TCR. Furthermore, analysis of a series of CD3'y truncation mutants indicated that in addition to S126 phosphorylation a motif C-terminal of S126 was required for TCR down-regulation. Point mutation analyses confirmed this observation and demonstrated that a membrane-proximal di-leucine motif (L131 and L132) in the cytoplasmic tail of CD3'y was required for PKC-mediated TCR downregulation in addition to phosphorylation at S126. Incubation of T cells in hypertonic medium known to disrupt normal clathrin lattices severely inhibited PKCmediated TCR down-regulation in non-mutated T cells, indicating that the TCR was down-regulated by endocytosis via clathrin coated pits. Based on the present results and previously published observations on intracellular receptor sorting, a general model for intracellular sorting of receptors containing di-leucineor tyrosine-based motifs is proposed.

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Section: Discussionsupporting

confidence: 53%

Section: Jgn-wt Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor.

et al. 1994

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“…Previous studies have indirectly indicated that TCR triggering induces TCR degradation (55)(56)(57), and this has later been directly confirmed (21,22,32). In agreement with this, we found that TCR triggering resulted in a dose-dependent increase in TCR degradation with a close-to-maximal degradation rate constant of ϳ0.0033 min Ϫ1 , resulting in a decrease in the TCR half-life to 3.5 h in both Jurkat cells and primary T cells.…”

Section: Discussionmentioning

confidence: 71%

Constitutive and Ligand-Induced TCR Degradation

Essen

Bonefeld

Siersma

et al. 2004

The Journal of Immunology

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Modulation of TCR expression levels is a central event during T cell development and activation, and it probably plays an important role in adjusting T cell responsiveness. Conflicting data have been published on down-regulation and degradation rates of the individual TCR subunits, and several divergent models for TCR down-regulation and degradation have been suggested. The aims of this study were to determine the rate constants for constitutive and ligand-induced TCR degradation and to determine whether the TCR subunits segregate or are processed as an intact unit during TCR down-regulation and degradation. We found that the TCR subunits in nonstimulated Jurkat cells were degraded with rate constants of ∼0.0011 min−1, resulting in a half-life of ∼10.5 h. Triggering of the TCR by anti-TCR Abs resulted in a 3-fold increase in the degradation rate constants to ∼0.0033 min−1, resulting in a half-life of ∼3.5 h. The subunits of the TCR complex were down-regulated from the cell surface and degraded with identical kinetics, and most likely remained associated during the passage throughout the endocytic pathway from the cell surface to the lysosomes. Similar results were obtained in studies of primary human Vβ8+ T cells stimulated with superantigen. Based on these results, the simplest model for TCR internalization, sorting, and degradation is proposed.

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“…The four Cys-Cys-His-His-type zinc fingers in the carboxyl terminus are involved in DNA and RNA binding, nuclear localization and proteinprotein interactions (Madden et al, 1993;Reddy and Licht, 1996;Lee and Haber, 2001). There are at least 24 different forms of WT1 that arise through alternative splicing, RNA editing and three translation-initiation starts sites, resulting in four predominant protein isoforms that differ by the presence of 17 amino acids between the activation/repression and zinc finger domains, and a three-amino-acid insert (KTS) that exists between the third and fourth zinc fingers (Haber et al, 1991;Telerman et al, 1992). The different isoforms are referred to as A, B, C and D, where A lacks both the 17 aa and KTS inserts, B contains the 17 aa insert but lacks KTS, C lacks the 17 aa but contains KTS, and D contains both the 17 aa and KTS inserts.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional activation of c-myc proto-oncogene by WT1 protein

et al. 2004

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The Wilms' tumor 1 gene (WT1) plays an essential role in urogenital development and malignancy. Through DNA binding, WT1 can either enhance or repress transcription depending on the context of the DNA-binding sites or the cell type in which it is expressed. WT1 is overexpressed in a variety of human cancers, including leukemia and breast cancer; in these diseases, the expression of WT1 is associated with a poor prognosis. To determine how WT1 affects c-myc expression in the context of breast cancer cells, we have examined the ability of both endogenous and exogenous WT1 proteins in breast cancer cells to bind to the c-myc promoter in vivo. Using c-myc-promoterdriven luciferase constructs, we found that different forms of WT1 could enhance the expression of the reporter. Unlike other studies where WT1 is reported to be a negative regulator of c-myc, we found that both the À and þ KTS forms of WT1 could act to enhance c-myc expression, depending on the cell type. The WT1-binding site near the second major transcription start site of the cmyc promoter was confirmed to be involved in upregulation of human c-myc by WT1. Finally, we demonstrated that overexpression of WT1 induced a significant increase in the abundance of endogenous c-myc protein in breast cancer cells, consistent with the upregulation of c-myc transcription following WT1 induction. These observations strongly argue that in the case of breast cancer WT1 is functioning as an oncogene in part by stimulating the expression of c-myc.

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Internalization of human T lymphocyte receptors

Cited by 67 publications

References 32 publications

CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor.

CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor.

Constitutive and Ligand-Induced TCR Degradation

Transcriptional activation of c-myc proto-oncogene by WT1 protein

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