scholarly journals Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation.

1996 ◽  
Vol 184 (2) ◽  
pp. 365-376 ◽  
Author(s):  
V A Boussiotis ◽  
D L Barber ◽  
B J Lee ◽  
J G Gribben ◽  
G J Freeman ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Specific Protein ◽  
Protein Tyrosine ◽  
Potential Applications

When stimulated through their antigen receptor, without costimulation, T cells enter a state of antigen-specific unresponsiveness, termed anergy. B7-mediated costimulation, signaling via CD28, is sufficient to prevent the induction of anergy. Here we show that ligation of T cell receptor (TCR) by alloantigen alone, which results in anergy, activates tyrosine phosphorylation of TCR zeta and its association with fyn. In contrast, TCR ligation in the presence of B7 costimulation, which results in productive immunity, activates tyrosine phosphorylation of TCR zeta and CD3 chains, which associate with activated lck and zeta-associated protein (ZAP) 70. Under these conditions, CD28 associates with activated lck and TCR zeta. These data suggest that the induction of anergy is an active signaling process characterized by the association of TCR zeta and fyn. In addition, CD28-mediated costimulation may prevent the induction of anergy by facilitating the effective association of TCR zeta and CD3 epsilon with the critical protein tyrosine kinase lck, and the subsequent recruitment of ZAP-70. Strategies to inhibit or activate TCR-associated, specific protein tyrosine kinase-mediated pathways may provide a basis for drug development with potential applications in the fields of transplantation, autoimmunity, and tumor immunity.

Investigation of the kinetics and order of tyrosine phosphorylation in the T-cell receptor zeta chain by the protein tyrosine kinase Lck

2003 ◽  
Vol 270 (11) ◽  
pp. 2369-2376 ◽  
Author(s):  
Hazel R. Housden ◽  
Paul J. S. Skipp ◽  
Matthew P. Crump ◽  
Robert J. Broadbridge ◽  
Tom Crabbe ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Protein Tyrosine ◽  
Zeta Chain

scholarly journals Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor

Nature ◽  
2007 ◽  
Vol 446 (7137) ◽  
pp. 824-824
Author(s):  
Marcos H. Hatada ◽  
Xiaode Lu ◽  
Ellen R. Laird ◽  
Jeremy Green ◽  
Jay P. Morgenstern ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Molecular Basis ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Protein Tyrosine

Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn)

Cell ◽  
1991 ◽  
Vol 65 (2) ◽  
pp. 281-291 ◽  
Author(s):  
Michael P. Cooke ◽  
Kristin M. Abraham ◽  
Katherine A. Forbush ◽  
Roger M. Perimutter
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
Protein Tyrosine ◽  
Family Protein ◽  
T Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals ZAP-70 Association with T Cell Receptor ζ (TCRζ): Fluorescence Imaging of Dynamic Changes upon Cellular Stimulation

1998 ◽  
Vol 143 (3) ◽  
pp. 613-624 ◽  
Author(s):  
Joanne Sloan-Lancaster ◽  
John Presley ◽  
Jan Ellenberg ◽  
Tetsuo Yamazaki ◽  
Jennifer Lippincott-Schwartz ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Specific Interaction ◽  
Active Form ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Protein Tyrosine

The nonreceptor protein tyrosine kinase ZAP-70 is a critical enzyme required for successful T lymphocyte activation. After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. The kinetics of its translocation to the cell surface, the properties of its specific interaction with the TCRζ chain expressed as a chimeric protein (TTζ and Tζζ), and its mobility in different intracellular compartments were studied in individual live HeLa cells, using ZAP-70 and Tζζ fused to green fluorescent protein (ZAP-70 GFP and Tζζ–GFP, respectively). Time-lapse imaging using confocal microscopy indicated that the activation-induced redistribution of ZAP-70 to the plasma membrane, after a delayed onset, is of long duration. The presence of the TCRζ chain is critical for the redistribution, which is enhanced when an active form of the protein tyrosine kinase Lck is coexpressed. Binding specificity to TTζ was indicated using mutant ZAP-70 GFPs and a truncated ζ chimera. Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. Tζζ– GFP is relatively immobile, while peripherally located ZAP-70 in stimulated cells is less mobile than cytosolic ZAP-70 in unstimulated cells, a phenotype confirmed by determining the respective diffusion constants. Examination of the specific molecular association of signaling proteins using these approaches has provided new insights into the TCRζ–ZAP-70 interaction and will be a powerful tool for continuing studies of lymphocyte activation.

Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor

Nature ◽  
1995 ◽  
Vol 377 (6544) ◽  
pp. 32-38 ◽  
Author(s):  
Marcos H. Hatada ◽  
Xiaode Lu ◽  
Ellen R. Laird ◽  
Jeremy Green ◽  
Jay P. Morgenstern ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Molecular Basis ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Protein Tyrosine

scholarly journals Identification, cloning, and characterization of a novel human T-cell- specific tyrosine kinase located at the hematopoietin complex on chromosome 5q

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1561-1572 ◽  
Author(s):  
S Gibson ◽  
B Leung ◽  
JA Squire ◽  
M Hill ◽  
N Arima ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Phosphorylation Site ◽  
Cell Receptor ◽  
Cytokine Receptors

Signal transduction through the T-cell receptor and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. Because neither the T-cell receptor nor cytokine receptors contain intrinsic kinase domains, signal transduction is thought to occur via association of these receptors with intracellular protein tyrosine kinases. Although several members of the SRC and SYK families of tyrosine kinases have been implicated in signal transduction in lymphocytes, it seems likely that additional tyrosine kinases involved in signal transduction remain to be identified. To identify unique T-cell tyrosine kinases, we used polymerase chain reaction-based cloning with degenerate oligonucleotides directed at highly conserved motifs of tyrosine kinase domains. We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. The cDNA of EMT predicts an open reading frame of 1866 bp encoding a protein with a predicted size of 72 Kd, which is in keeping with its size on Western blotting. A single 6.2-kb EMT mRNA and 72-Kd protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages. EMT contains both SH2 and SH3 domains, as do many other intracellular kinases. EMT does not contain the N-terminal myristylation site or the negative regulatory tyrosine phosphorylation site in its carboxyterminus that are found in the SRC family of tyrosine kinases. EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase. Sequence comparison suggests that EMT is likely the human homologue of a recently identified murine interleukin-2 (IL-2)-inducible T cell kinase (ITK). However, unlike ITK, EMT message and protein levels do not vary markedly on stimulation of human IL-2-responsive T cells with IL-2. Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII. EMT was localized to chromosome 5q31–32, a region that contains the genes for several growth factors and receptors as well as early activation genes, particularly those involved in the hematopoietic system. Furthermore, the 5q31–32 region is implicated in the genesis of the 5q- syndrome associated with myelodysplasia and development of leukemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Protein tyrosine kinase p56lck controls allelic exclusion of T-cell receptor β-chain genes

Nature ◽  
1993 ◽  
Vol 365 (6446) ◽  
pp. 552-554 ◽  
Author(s):  
Steven J. Anderson ◽  
Steven D. Levin ◽  
Roger M. Perlmutter
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Allelic Exclusion ◽  
Protein Tyrosine ◽  
Β Chain

scholarly journals Constitutive tyrosine phosphorylation of the T-cell receptor (TCR) zeta subunit: regulation of TCR-associated protein tyrosine kinase activity by TCR zeta.

1993 ◽  
Vol 13 (9) ◽  
pp. 5771-5780 ◽  
Author(s):  
N S van Oers ◽  
W Tao ◽  
J D Watts ◽  
P Johnson ◽  
R Aebersold ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Total Cell ◽  
Zeta Chain

The T-cell receptor (TCR) zeta subunit is an important component of the TCR complex, involved in signal transduction events following TCR engagement. In this study, we showed that the TCR zeta chain is constitutively tyrosine phosphorylated to similar extents in thymocytes and lymph node T cells. Approximately 35% of the tyrosine-phosphorylated TCR zeta (phospho zeta) precipitated from total cell lysates appeared to be surface associated. Furthermore, constitutive phosphorylation of TCR zeta in T cells occurred independently of antigen stimulation and did not require CD4 or CD8 coreceptor expression. In lymph node T cells that constitutively express tyrosine-phosphorylated TCR zeta, there was a direct correlation between surface TCR-associated protein tyrosine kinase (PTK) activity and expression of phospho zeta. TCR stimulation of these cells resulted in an increase in PTK activity that coprecipitated with the surface TCR complex and a corresponding increase in the levels of phospho zeta. TCR ligations also contributed to the detection of several additional phosphoproteins that coprecipitated with surface TCR complexes, including a 72-kDa tyrosine-phosphorylated protein. The presence of TCR-associated PTK activity also correlated with the binding of a 72-kDa protein, which became tyrosine phosphorylated in vitro kinase assays, to tyrosine phosphorylated TCR zeta. The cytoplasmic region of the TCR zeta chain was synthesized, tyrosine phosphorylated, and conjugated to Sepharose beads. Only tyrosine-phosphorylated, not nonphosphorylated, TCR zeta beads were capable of immunoprecipitating the 72-kDa protein from total cell lysates. This 72-kDa protein is likely the murine equivalent of human PTK ZAP-70, which has been shown to associate specifically with phospho zeta. These results suggest that TCR-associated PTK activity is regulated, at least in part, by the tyrosine phosphorylation status of TCR zeta.

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