Genetic Evidence for Differential Coupling of Syk Family Kinases to the T-Cell Receptor: Reconstitution Studies in a ZAP-70-Deficient Jurkat T-Cell Line

Williams, Brandi L.; Schreiber, Kathy L.; Zhang, Weiguo; Wange, Ronald L.; Samelson, Lawrence E.; Leibson, Paul J.; Abraham, Robert T.

doi:10.1128/mcb.18.3.1388

Cited by 249 publications

(302 citation statements)

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“…7D). To further explore the upregulation of CD69 surface expression by ORF5, we expressed ORF5 in Lck-deficient J.CaM1 cells, SLP-76-defient J14-v-29 cells, and ZAP70-deficient P116 cells, which were derived from Jurkat T cells (49,56,59). In contrast to its activity in parental Jurkat T cells, ORF5 expression was incapable of inducing the upregulation of CD69 surface expression in Lck-deficient J.CaM1 cells and SLP-76-defient J14-v-29 cells, indicating that Lck and SLP-76 are required for ORF5's ability to induce CD69 surface expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-B, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.Upon engagement of the T-cell antigen receptor (TCR), many cellular proteins, including TCR subunits, adaptor proteins, and other effector molecules, are phosphorylated and subsequently are involved in the formation of molecular complexes at the site of contact with the antigen-presenting cells (33, 51, 54) The earliest signaling event following TCR engagement is the sequential activation of the non-receptor protein tyrosine kinases (PTKs) of the Src and Syk families. Activated Src family PTKs, Lck and Fyn, in T cells subsequently phosphorylate tyrosine residues within a consensus sequence termed the immunoreceptor tyrosine-based activation motif in the cytosolic tails of the TCR subunits. The phosphorylated immunoreceptor tyrosine-based activation motifs of TCR in turn recruit the Syk family PTKs ZAP70 and Syk through their Src homology 2 (SH2) domains (33). Together with Lck and Fyn, the ZAP70 and Syk kinases then promote the phosphorylation of many intracellular signaling molecules, including phospholipase C-␥1 (PLC-␥1), Cbl, Vav, LAT (linker for activation of T cells) and SLP-76 (SH2-containing leukocyte protein-76) (12,25,41,45,46,53). Phosphorylation of these cellular signaling molecules ultimately induces various cellular events such as cytoskeletal alteration, intracellular Ca ϩϩ influx, transcription factor activation, and cytokine/chemokine production (4,20,38,43,59).Two adaptor proteins, LAT and SLP-76, have been shown to be critical for the optimal activation of T cells and to function in linking proximal signaling events to distal downstream signaling ac...

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Section: Resultsmentioning

confidence: 99%

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Lee

Chung

Cho

et al. 2004

Molecular and Cellular Biology

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“…Since Zap-70 is also required for TCRinduced PLCg1 phosphorylation (Williams et al, 1998(Williams et al, , 1999, one can speculate that Zap-70 itself is responsible for the phosphorylation of PLCg1. PLCg1, however, does not appear to be a direct substrate of Zap-70 (Veri et al, 2001) and no increase in Zap-70 phosphorylation or kinase activity has been observed in Jurkat cells expressing 70Z/3 Cbl (van Leeuwen et al, 1999a, b;Zhang et al, 1999a, b), making it unlikely that 70Z/3 Cbl alters the kinase activity of Zap-70.…”

Section: Discussionmentioning

confidence: 99%

“…Additional evidence for a Zap-70 requirement in the effect of 70Z/3Cbl on PLCg1 phosphorylation was obtained by expressing WT PLCg1-HA together with either 70Z/3 Cbl or pCI-neo in the Zap-70-deficient Jurkat cell line P116 (Williams et al, 1998), and comparing the effect to that observed in P116 cells stably reconstituted with Zap-70. At equivalent levels of 70Z/3 Cbl expression, no PLCg1 phosphorylation was detected in either unstimulated or TCR-triggered P116 70Z/3 Cbl-induced NFAT activation requires Zap-70 but is independent of Slp-76…”

Section: The Effect Of 70z/3 Cbl On Plcg1 Phosphorylation Requires Zamentioning

confidence: 99%

“…A CD3-high Jurkat T-cell line was as previously described . The Zap-70 negative (P116) and reconstituted cell lines were from Dr RT Abraham (Duke University, Durham, NC, USA) (Williams et al, 1998). The Slp-76 deficient (J14-v-29) and reconstituted (J14-76-11) clones as well as the anti-TCR antibody C305 were from Dr A Weiss (UCSF, San Francisco, CA, USA) (Yablonski et al, 1998).…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

“…In T cells, the PLCg1-regulated Ca 2 þ mobilization controls Ca 2 þ -dependent transcriptional events that govern cellular responses, such as cytokine production (Wange and Samelson, 1996). T-cell receptor (TCR)-induced PLCg1 activation is controlled by nonreceptor protein tyrosine kinases, including Lck and Zap-70 (Williams et al, 1998(Williams et al, , 1999Kane et al, 2000), the phosphorylation of the adapters Lat and Slp-76 (Yablonski et al, 1998;Zhang et al, 1999a, b), and the tyrosine phosphorylation of PLCg1 itself (Todderud et al, 1990;Kim et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism

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Signal Transduction During Natural Killer Cell Activation

Chini

Leibson

2000

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Natural killer (NK) cells are a subpopulation of lymphocytes that can mediate cytotoxicity of certain tumor cells, virus-infected cells, and normal cells. In addition to their cytotoxic potential, NK cells secrete a variety of cytokines and chemokines that can modulate the function, growth, and differentiation of other immune cells. These different responses are initiated by the interaction of specific NK surface receptors with defined soluble or cell-associated ligands. There are several different types of receptors on the NK cell surface including "triggering" receptors, adhesion molecules, cytokine receptors, and MHC-recognizing killer-cell inhibitory receptors. The functional response of an NK cell is the result of the integration of signals transduced by these different types of receptors. Some of these signaling pathways are similar to other lymphoid cells, but there are also unique features employed by NK cells. This overview focuses on receptor-initiated signaling pathways that modulate NK functions.

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Genetic Evidence for Differential Coupling of Syk Family Kinases to the T-Cell Receptor: Reconstitution Studies in a ZAP-70-Deficient Jurkat T-Cell Line

Abstract: T-cell antigen receptor (TCR) engagement activates multiple protein tyrosine kinases (PTKs),

Cited by 249 publications

References 67 publications

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

Modulation of T-Cell Receptor Signal Transduction by Herpesvirus Signaling Adaptor Protein

70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism

Signal Transduction During Natural Killer Cell Activation

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