International Immunology, Vol. 11, No. 6, 943-950,
June 1999
© 1999 Japanese Society for Immunology
Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line
Section on Lymphocyte Signaling, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-5430, USA
1 Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
Correspondence to: L. E. Samelson
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Abstract |
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The adaptor molecule LAT (linker for activation of T cells) is a palmitoylated integral membrane protein that localizes to the glycolipid-enriched microdomains in the plasma membrane. Upon TCR engagement, LAT becomes phosphorylated on multiple tyrosine residues and then binds several critical signaling molecules. Here, we describe the generation and characterization of a LAT-deficient cell line. Using this cell line, we demonstrate that LAT is required for TCR-mediated Ca2+ mobilization and optimal tyrosine phosphorylation of phospholipase C-
1, Vav and SLP-76. LAT is also required for Erk activation, CD69 up-regulation, and AP- and NFAT-mediated gene transcription. We also demonstrate, by reconstituting this cell line with LAT mutants, that the LAT transmembrane domain and palmitoylation at Cys26, but not Cys29, are required for LAT function and TCR signaling. These studies provide further evidence for the crucial role of the LAT molecule, and demonstrate the use of a LAT-deficient cell line for the analysis of LAT structure and function.
Keywords: LAT, TCR, tyrosine phosphorylation, palmitoylation
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Introduction |
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Many of the early biochemical events that result from engagement of the TCR are now well characterized (1,2). Following antigen stimulation or anti-TCR antibody cross-linking, protein tyrosine kinases (PTK) of the Src family of PTK, Lck and/or Fyn, phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs in the cytosolic tails of the TCR
or CD3 subunits. These immunoreceptor tyrosine-based activation motifs are characterized by two repeated sequences, Tyr–X–X–Leu/Ile, separated by 10–12 amino acids. Phosphorylation of these tyrosines creates a binding site for the tandem SH2 domains of the ZAP-70 PTK. Subsequent phosphorylation of ZAP-70 by the Src kinases results in activation of ZAP-70. Following these rapid events, the activated PTK at the engaged TCR phosphorylate a number of proteins that can be divided into two categories: linker or adaptor proteins that bind other proteins either constitutively or following modification, such as tyrosine phosphorylation and enzymes that are regulated by tyrosine phosphorylation (3,4).
The LAT (linker for activation of T cells) molecule is a critical linker molecule phosphorylated on multiple tyrosine residues after TCR engagement (5). LAT is an integral membrane protein, and its phosphorylation results in recruitment and binding by the SH2 domain of the cytosolic Grb2 molecule. Bound to the SH3 domains of Grb2 are a number of other linkers and enzymes including SOS (an activator of Ras), Cbl, a complex of proteins including SLP-76, SLAP, Vav (an activator of Rac) and others. Some of these proteins are themselves brought together by specific phosphorylation induced by the activated PTK. LAT also binds phospholipase C (PLC)-1 and phosphatidylinositol-3-kinase. The binding of these proteins to LAT appears to be critical to TCR-mediated signaling. Mutation of two tyrosine residues in the cytosolic tail of LAT inhibits binding of all the proteins identified above. Overexpression of this LAT mutant blocks TCR-induced activation as measured by an inhibition of activation of two transcription factors, NFAT and AP-1, critical to induction of IL-2 production (5).
A recent set of observations confirms and extends these conclusions (6). The J.CaM2 variant of Jurkat was generated by mutagenesis over a decade ago (7). Engagement of its TCR results in tyrosine phosphorylation of the TCR and some substrates such as Cbl, while other proteins such as PLC-1 and SLP-76 show deficient phosphorylation. The cells fail to show an elevation of intracellular calcium, activation of Ras or Erk, and transcriptional activation of NFAT and AP-1 does not occur. These cells were shown to lack LAT protein and expression of LAT resulted in reconstitution of all of the deficient signaling events.
Further analysis of the LAT molecule reveals that it is palmitoylated at two cysteine residues near the transmembrane region (Cys26 and Cys29) (8). The combination of its transmembrane domain and palmitoylation, especially at Cys26, targets the LAT molecule to specialized subdomains of the plasma membrane known as membrane rafts or glycolipid-enriched microdomains. LAT mutants that are not palmitoylated at Cys26 do not target to these microdomains. The functional significance of raft targeting is demonstrated by the failure of this LAT mutant to be phosphorylated following TCR engagement.
While the J.CaM2 cell was under investigation, we performed an independent mutagenesis and screening experiment in the hope of finding LAT-deficient variants of Jurkat. In this study we describe such a LAT-deficient T cell line, ANJ3, and show that it has a similar phenotype as J.CaM2. It is severely compromised in signaling events mediated by the TCR and we demonstrate that reconstitution with wild-type LAT restores normal responses. We also use this cell line to test the hypothesis that LAT targeting to plasma membrane microdomains is central to normal signaling processes. For this we stably express LAT mutants that are not appropriately palmitoylated and show that they fail to reconstitute TCR-mediated signaling.
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Methods |
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Cell culture, antibodies and immunoprecipitation
Jurkat cells (E6.1) and LAT-deficient cells (ANJ3) were maintained in RPMI 1640 supplemented with 10% FCS. Procedures for random chemical mutagenesis of the Jurkat E6.1 T cell line, as well as selection of mutants deficient in calcium signaling, were defined previously (9). The antibodies used in the experiments were: rabbit polyclonal anti-LAT (5), anti-ZAP-70 (10), anti-SLP-76 (a gift from Dr A. Chan), anti-CD3
(OKT3), monoclonal anti-myc (9E10), monoclonal anti-PLC-1 (a gift from Dr. S. Rhee), anti-Erk2 from Santa Cruz Biotechnology (Santa Cruz, CA), and anti-Vav and anti-phosphotyrosine (4G10) from Upstate Biotechnology (Lake Placid, NY). For immunoprecipitation, Jurkat cells (108 cells/ml) were either stimulated with OKT3 ascites (1:100) for 2 min or left untreated. Cells were lysed in ice-cold lysis buffer (1% Brij, 25 mM Tris, 150 mM NaCl and 5 mM EDTA) before immunoprecipitation. Protein samples were resolved on SDS–PAGE, transferred to nitrocellulose and immunoblotted with mAb or antisera. Immunoreactive proteins were detected with horseradish peroxidase-coupled secondary antibody followed by ECL (Amersham, Arlington Heights, IL).
Transfection of Jurkat cells
For stable transfection of Jurkat cells (ANJ3), 107 cells in 0.4 ml RPMI 1640, 25 mM HEPES and 2 mM glutamine were incubated with 15 µg of plasmid DNA, electroporated with a BioRad GenePulser (310V, 960 µF) and selected in the presence of 1.5 mg/ml G418.
Analysis of CD3 and CD69 expression
For CD3 expression, Jurkat cells were stained with anti-CD3 antibody (OKT3) for 30 min, washed and then stained with FITC-conjugated anti-mouse antibody for 30 min. These cells were washed again and analyzed by FACScan (Becton Dickinson, San Jose, CA). For CD69 expression, cells were either left unstimulated or stimulated with OKT3 for 16 h. Cells were stained with FITC-conjugated anti-CD69 antibody, washed and analyzed by FACScan.
Ca2+ flux, luciferase assay and Erk kinase assay
The measurement for intracellular free Ca2+ and luciferase assay were performed as described (9). The AP-1 reporter plasmid was kindly provided by Dr D. McKean (Mayo Clinic). For the Erk kinase assay, Jurkat cells were stimulated with OKT3 for 15 min or left unstimulated. Anti-Erk2 immunoprecipitates were resuspended in the kinase reaction buffer (20 mM Tris–HCl, pH 7.6, 13 mM MgCl2 and 1.5 mM EGTA). The kinase reaction was performed using 10 µg myelin basic protein (MBP) and 5 µCi [-32P]ATP per reaction.
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Results |
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Isolation and reconstitution of a LAT-deficient Jurkat clone
Mutagenesis of Jurkat T cells followed by selection for cells that fail to flux calcium following TCR or pervanadate treatment has led to the identification of a number of mutants with defects in proteins critical to TCR-mediated signaling (7,9,11) This approach was also used to identify Jurkat variants deficient in LAT. Wild-type Jurkat cells were mutagenized with the frame shift mutagen, ICR-191, and cells that failed to mobilize Ca2+ in response to pervanadate were selected. The resulting bulk population was subcloned and individual clones were screened by blotting with an anti-LAT antibody. Three clones were non-responsive to pervanadate and deficient in LAT expression (not shown). One of these, ANJ3, was chosen for further analysis. Stimulation with the anti-CD3
antibody OKT3 (Fig. 1A and B
) failed to induce calcium mobilization and it was deficient in LAT expression (Fig. 2, lanes 3 and 4, lower panel). To confirm that the failure of Ca2+ mobilization was due to loss of LAT, ANJ3 cells were transfected with an expression vector containing a myc-tagged LAT cDNA. Stably transfected clones with a similar level of LAT expression were selected for further analysis (Fig. 2, lane 5 and 6, lower panel). TCR expression was confirmed by flow cytometry (Fig. 3A). myc-tagged LAT migrated on SDS–PAGE as a doublet of 36–38 kDa. Reconstitution of ANJ3 with wild-type LAT, designated as ANJ3+LAT(wt), restored the Ca2+ mobilization response to anti-CD3 antibody stimulation (Fig. 1C).
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LAT reconstitution restores the optimal tyrosine phosphorylation of PLC-
1, Vav and SLP-76To confirm the role of LAT in regulating the tyrosine phosphorylation of intracellular proteins during TCR engagement, Jurkat (E6.1), ANJ3 and ANJ3 transfectants reconstituted with wild-type LAT were stimulated with OKT3, and PTK substrates were detected by probing with anti-phosphotyrosine antibody (Fig. 2
, top panel). The tyrosine phosphorylated LAT molecule was not detected in cellular lysates prepared from ANJ3 cells (Fig. 2, lane 4), but this species was observed in the reconstituted cells (Fig. 2, lane 6). Tyrosine phosphorylation of proteins likely to be PLC-1 (135 kDa),Vav (100 kDa) and SLP-76 (76 kDa) was also reduced in ANJ3 cells. Tyrosine phosphorylation of other cellular proteins such as Cbl and ZAP-70 seemed normal. Importantly, reconstitution of LAT in ANJ3 restored the tyrosine phosphorylation of these proteins observed in activated cells (Fig. 2, lane 5 and 6).
Direct immunoprecipitation of these proteins was then performed to provide definitive identification. As shown in Fig. 4(A), OKT3 stimulation induced the tyrosine phosphorylation of LAT from normal Jurkat (E6.1) and ANJ3 reconstituted with LAT. Surprisingly, there was a small amount of tyrosine phosphorylated LAT immunoprecipitated from ANJ3, indicating that ANJ3 was not totally deficient in LAT expression. Immunoprecipitation of ZAP-70 showed that the tyrosine phosphorylation of ZAP-70 upon stimulation was similar in these cells, but basal tyrosine phosphorylation of ZAP-70 in ANJ3 cells was higher (Fig. 4B). Immunoprecipitation of Vav, SLP-76 and PLC-1 from stimulated ANJ3 cells showed reduced tyrosine phosphorylation (Fig. 4C–E). The basal phosphorylation of SLP-76 was also reduced in ANJ3. Reconstitution with LAT restored the tyrosine phosphorylation of these proteins following TCR ligation. Immunoprecipitation of Vav also revealed association of SLP-76 as previously described (Fig. 4C). The impact of LAT expression on tyrosine phosphorylation of PLC-1 in ANJ3 was demonstrated in Fig. 4(E). PLC-1 could still be phosphorylated in ANJ3 upon OKT3 stimulation, but at a reduced level compared to wild-type Jurkat. The defect in PLC-1 phosphorylation was fully reversed in ANJ3 reconstituted with LAT. Immunoprecipitation of PLC-1 also showed the presence of associated tyrosine phosphorylated LAT upon stimulation as previously described. There was no tyrosine phosphorylated LAT found in anti-PLC-1 immunoprecipitates from ANJ3 cells. The tagged transfected LAT co-precipitated with PLC-1 in the reconstituted cells.
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LAT involvement in CD69 up-regulation and Erk activation after TCR stimulation
CD69 is a marker for T cell activation and its expression is induced in a Ras-dependent manner following anti-TCR or phorbol myristate acetate (PMA) stimulation (12). Since LAT forms a complex with Grb2 and SOS, we reasoned that the activation of Ras pathway might be affected by the absence of LAT. We first tested whether LAT is involved in up-regulation of CD69. As shown in Fig. 3
, anti-CD3 stimulation induced CD69 up-regulation in Jurkat E6.1 cells (Fig. 3B), but failed to induce CD69 expression in ANJ3 cells (Fig. 3C). However, expression of CD69 in ANJ3 cells could be induced following reconstitution of this cell with the LAT molecule (Fig. 3D).
We next examined the effect of LAT deficiency on Erk activation by performing in vitro kinase assays on anti-Erk2 immunoprecipitates from unstimulated or OKT3-stimulated E6.1, ANJ3 and ANJ3+LAT(wt). As shown in Fig. 5, Erk was activated in normal Jurkat T cells (Fig. 5, lane 1 and 2), but there was very little Erk activation in ANJ3 cells (Fig. 5, lane 3 and 4). Reconstitution of ANJ3 with LAT restored receptor-mediated Erk activation (Fig. 5, lane 5 and 6). Together the CD69 and Erk studies show that these pathways, both downstream of Ras activation in T cells, are dependent on LAT.
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LAT in TCR-dependent transcriptional activation
Engagement of the TCR leads to activation of Ras and Ca2+ pathways and eventually leads to activation of AP-1 and NFAT-mediated transcriptional activation. Because LAT resulted in a marked impairment of calcium mobilization and pathways coupled to Ras activation, we predicted that transcriptional activation would also be inhibited. To confirm that LAT is involved in TCR-mediated activation of AP-1 and NFAT, we transiently transfected E6.1, ANJ3 and ANJ3+LAT(wt) with pAP-1-Luc or pNFAT-luc reporter plasmids which contain multiple copies of AP-1 or NFAT binding sites. Transfected cells were either left unstimulated, or stimulated with OKT3, or with PMA + ionomycin. Luciferase activity was normalized to the level of PMA + ionomycin stimulation. As shown in Fig. 6
, there was no AP-1 or NFAT transcriptional activation following OKT3 stimulation of ANJ3 cells. These defects were corrected by reconstitution of these cells with LAT.
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Tyrosine phosphorylation of LAT with mutations at palmitoylation sites in ANJ3 cells
Our previous studies showed that LAT palmitoylation at C26 is required for targeting LAT to glycolipid-enriched microdomains and LAT tyrosine phosphorylation (8). To further study the functional role of LAT palmitoylation in TCR signaling, we used ANJ3 cells to make stable transfectants with the LAT C26A, C29A and transmembrane domain-truncation (
tm) mutants. As shown in Fig. 7A, we selected clones expressing amounts of LAT similar to wild-type Jurkat E6.1 by blotting the whole cell lysates from those transfectants with anti-LAT antibody. These clones also express similar amounts of CD3 (not shown). Interestingly, unlike wild-type or C29A LAT which can be observed to migrate on SDS–PAGE as two species, the C26A mutant was predominantly found in one 38 kDa form (Fig. 7A), suggesting that palmitoylation at C26 is required for generation of the p36 form of LAT. After the stable transfectants were either stimulated with OKT3 or left unstimulated, LAT was immunoprecipitated using the anti-myc antibody. As shown in Fig. 7B, wild-type and C29A LAT were tyrosine phosphorylated after stimulation. The tyrosine phosphorylation of cellular proteins in C29A was indistinguishable from that in wild-type Jurkat (not shown). In contrast, cells expressing C26A and LATtm showed either no increase or very little increase in tyrosine phosphorylation of the mutant LAT. This result is consistent with our previous result using transient transfection to express these mutants in Jurkat cells.
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LAT palmitoylation and TCR-mediated signaling
These stable transfectants were then tested to determine whether TCR engagement induced normal signaling events. We predicted that the LAT C29A mutant would have a similar response as wild-type, but that the C26A and LAT
tm would be defective. We first examined the tyrosine phosphorylation of PLC-1 (Fig. 7C). As shown previously, the LAT-deficient ANJ3 showed some increase in phosphorylation of this protein following TCR engagement, but far less than in Jurkat E6.1 or in LAT-reconstituted cells. Transfection of ANJ3 with C29A also restored tyrosine phosphorylation to the level seen in wild-type E6.1 and ANJ3 transfected with wild-type LAT. Transfection of C26A and LATtm failed to result in enhanced PLC-1 tyrosine phosphorylation after TCR engagement. Ca2+ mobilization in these transfectants was then tested and results were as predicted from these PLC-1 phosphorylation data. As shown in Fig. 1E, expression of the C29A mutant LAT could restore Ca2+ mobilization in ANJ3 cells, while C26A and LATtm could not (Fig. 1D and F).
Events coupled to the Ras pathway were also examined in these stable transfectants. Only those clones expressing wild-type or the C29A LAT mutant showed CD69 expression upon OKT3 stimulation (data not shown). As shown in Fig. 5, only reconstitution with the wild-type or C29A LAT allowed an increase in Erk kinase activity (Fig. 5, lanes 9 and 10). There was very little if any increase of Erk activation in ANJ3 cells or ANJ3 cells transfected with C26A and LATtm (Fig. 5, lanes 7, 8, 11, and 12).
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Discussion |
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For many years the pp36–38 molecule, now known as LAT, had been thought to have an important function as a linker molecule that, after phosphorylation, was capable of binding several signaling proteins, and coupling Ras and Ca2+ pathways to the activated TCR (13–15). Cloning and further characterization of LAT allowed us to test this hypothesis (5). Upon tyrosine phosphorylation, LAT interacts with PLC-
1, phophotidylinositol-3-kinase, Grb2 and other signaling molecules. The mutation of two critical tyrosine residues in LAT resulted in inhibition of the interaction with these molecules. The critical role of LAT and its ability to bind signaling molecules were shown by the inhibition of T cell activation produced by expressing this mutant form of LAT.
Additional evidence in support of LAT function was sought by generating and characterizing Jurkat cell line lacking the LAT protein. As discussed above, a mutant variant of Jurkat with a profound signaling defect, J.CaM2, was recently demonstrated to lack LAT (6). While that cell line was under investigation, in parallel as a screen for such LAT-deficient cell lines, mutagenized Jurkat cells were activated with the tyrosine phosphatase inhibitor pervanadate, which increases the level of phosphorylated tyrosines and leads to an increase in intracellular calcium. Since receptor-mediated calcium elevation is dependent on both the tyrosine phosphorylation of PLC-1 and recruitment of this enzyme to LAT, we assumed that we would find mutant cell lines lacking LAT that would not flux calcium upon TCR engagement. Several such lines were established and one, ANJ3, was selected for further testing. LAT levels, determined by Western blotting, were at least 50 times less than the parental Jurkat (E6.1) and TCR engagement of this clone failed to produce calcium elevation. Further analysis of these cells revealed that, though ZAP-70 tyrosine phosphorylation was induced by receptor activation, phosphorylation of several substrates including PLC-1, SLP-76 and Vav was dramatically reduced. The restoration of tyrosine phosphorylation of these proteins in ANJ3 cells by reintroduction of LAT demonstrates that the signaling apparatus, including the TCR and PTK, function normally.
In addition to the inhibition of calcium elevation, the functional consequences of LAT deficiency include a decrease in ERK activation and CD69 induction. These events are dependent on the activation of Ras. Previous work demonstrates that LAT is responsible for recruitment of the Ras activator Sos via its interaction with Grb2. Without LAT the Ras pathway is not appropriately activated. That and the failure of calcium elevation results in the lack of AP-1 and NFAT activation. These transcription factors, whose activation is required for production of IL-2, depend on intact Ras and calcium pathways. The results obtained in the ANJ3 cell line are identical to those seen in J.CaM2 (6). Thus analysis of two independently derived LAT-deficient mutants of Jurkat provide strong evidence for the central function of this molecule.
A new area of research in the study of signaling via immunoreceptors is investigation of the function of plasma membrane microdomains (16,17). This membrane heterogeneity has been defined as detergent insolubility, although recently imaging techniques have been used to demonstrate these microdomains in living cells (18–20). The heterogeneity is due to self-association of glycosphingolipids and cholesterol, resulting in localized enrichment of particular lipids and proteins, which often are themselves acylated. These proteins include the Src family kinases, Lck and Fyn, which are involved in TCR activation (21,22). Two immunoreceptors have been shown to localize to such microdomains upon activation. These are the FcRI and, in the hands of some investigators, the TCR (16,17,23). Additionally, activation via the TCR results in enhanced recruitment and tyrosine phosphorylation of signaling molecules within the domains (8).
Studies addressing LAT intracellular localization revealed that the molecule is not only membrane localized, but also targeted to microdomains (8). Targeting is mediated by both a region likely to be a transmembrane domain, and dual cysteines at positions 26 and 29. A cysteine to alanine mutation at position 26 prevented LAT microdomain targeting, while mutation at 29 decreased it. The C26A mutation also resulted in a failure of LAT tyrosine phosphorylation following TCR cross-linking. The existence of a LAT-deficient cell line allowed us to test the hypothesis that LAT targeting to microdomains and subsequent tyrosine phosphorylation is critical to TCR-mediated signaling. These cells were transfected with LAT containing the C26 and C29 single mutations, and a mutant lacking the transmembrane domain. Reconstitution with the C29A mutant resulted in LAT tyrosine phosphorylation and restoration of TCR-mediated signaling. In contrast, neither the C26A nor the transmembrane deletion mutant demonstrated enhanced tyrosine phosphorylation upon TCR activation. Substrate phosphorylation was also impaired. PLC-1 showed a slight increase in tyrosine phosphorylation following TCR activation in ANJ3 cells. The enhanced PLC-1 tyrosine phosphorylation seen with activation in cells reconstituted with wild-type LAT was not observed in cells reconstituted with C26A or tm mutants. Signaling via PLC-1 in cells expressing these two mutants was markedly inhibited as demonstrated by the lack of calcium flux following TCR engagement. Similarly these two mutants failed to reconstitute Ras pathway function as shown by the minimal increase in ERK activation and the failure of CD69 induction following anti-CD3 stimulation. These results provide further evidence that LAT targeting to membrane microdomains is critical to its function as a linker molecule. Its failure to be tyrosine phosphorylated when it is not appropriately targeted results in a failure of recruitment of signaling molecules to appropriate intracellular locations.
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Acknowledgments |
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W. Z. is a fellow of the Leukemia Society of America. B. J. I and R. T. A. are supported by an NIH grant, GM47286.
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Abbreviations |
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| MBP | myelin basic protein |
| PMA | phorbol myristate acetate |
| PLC | phospholipase C |
| PTK | protein tyrosine kinase |
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Notes |
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2 Present address: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Transmitting editor: J. A. Bluestone
Received 9 February 1999, accepted 26 February 1999.
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K. Roget, M. Malissen, O. Malbec, B. Malissen, and M. Daeron Non-T Cell Activation Linker Promotes Mast Cell Survival by Dampening the Recruitment of SHIP1 by Linker for Activation of T Cells J. Immunol., March 15, 2008; 180(6): 3689 - 3698. [Abstract] [Full Text] [PDF]
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N. A. Luckashenak, R. L. Ryszkiewicz, K. D. Ramsey, and J. L. Clements The Src Homology 2 Domain-Containing Leukocyte Protein of 76-kDa Adaptor Links Integrin Ligation with p44/42 MAPK Phosphorylation and Podosome Distribution in Murine Dendritic Cells J. Immunol., October 15, 2006; 177(8): 5177 - 5185. [Abstract] [Full Text] [PDF]
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M. Zhu, I. Rhee, Y. Liu, and W. Zhang Negative Regulation of Fc{epsilon}RI-mediated Signaling and Mast Cell Function by the Adaptor Protein LAX J. Biol. Chem., July 7, 2006; 281(27): 18408 - 18413. [Abstract] [Full Text] [PDF]
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E. Ahn, H. Lee, and Y. Yun LIME acts as a transmembrane adapter mediating BCR-dependent B-cell activation Blood, February 15, 2006; 107(4): 1521 - 1527. [Abstract] [Full Text] [PDF]
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D. D. Sloan, J.-Y. Han, T. K. Sandifer, M. Stewart, A. J. Hinz, M. Yoon, D. C. Johnson, P. G. Spear, and K. R. Jerome Inhibition of TCR Signaling by Herpes Simplex Virus J. Immunol., February 1, 2006; 176(3): 1825 - 1833. [Abstract] [Full Text] [PDF]
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 I. C.A. Munnix, A. Strehl, M. J.E. Kuijpers, J. M. Auger, P. E.J. van der Meijden, M. A.M. van Zandvoort, M. G.A. oude Egbrink, B. Nieswandt, and J. W.M. Heemskerk The Glycoprotein VI-Phospholipase C{gamma}2 Signaling Pathway Controls Thrombus Formation Induced by Collagen and Tissue Factor In Vitro and In Vivo Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2673 - 2678. [Abstract] [Full Text] [PDF]
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J. C. D. Houtman, R. A. Houghtling, M. Barda-Saad, Y. Toda, and L. E. Samelson Early Phosphorylation Kinetics of Proteins Involved in Proximal TCR-Mediated Signaling Pathways J. Immunol., August 15, 2005; 175(4): 2449 - 2458. [Abstract] [Full Text] [PDF]
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R. Geyeregger, M. Zeyda, G. J. Zlabinger, W. Waldhausl, and T. M. Stulnig Polyunsaturated fatty acids interfere with formation of the immunological synapse J. Leukoc. Biol., May 1, 2005; 77(5): 680 - 688. [Abstract] [Full Text] [PDF]
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M. Zhu, S. Shen, Y. Liu, O. Granillo, and W. Zhang Cutting Edge: Localization of Linker for Activation of T Cells to Lipid Rafts Is Not Essential in T Cell Activation and Development J. Immunol., January 1, 2005; 174(1): 31 - 35. [Abstract] [Full Text] [PDF]
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M. Zhu, Y. Liu, S. Koonpaew, O. Granillo, and W. Zhang Positive and Negative Regulation of Fc{varepsilon}RI-Mediated Signaling by the Adaptor Protein LAB/NTAL J. Exp. Med., October 18, 2004; 200(8): 991 - 1000. [Abstract] [Full Text] [PDF]
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P. Volna, P. Lebduska, L. Draberova, S. Simova, P. Heneberg, M. Boubelik, V. Bugajev, B. Malissen, B. S. Wilson, V. Horejsi, et al. Negative Regulation of Mast Cell Signaling and Function by the Adaptor LAB/NTAL J. Exp. Med., October 18, 2004; 200(8): 1001 - 1013. [Abstract] [Full Text] [PDF]
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O. Malbec, M. Malissen, I. Isnardi, R. Lesourne, A.-M. Mura, W. H. Fridman, B. Malissen, and M. Daeron Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells J. Immunol., October 15, 2004; 173(8): 5086 - 5094. [Abstract] [Full Text] [PDF]
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H. Wang, F. E. McCann, J. D. Gordan, X. Wu, M. Raab, T. H. Malik, D. M. Davis, and C. E. Rudd ADAP-SLP-76 Binding Differentially Regulates Supramolecular Activation Cluster (SMAC) Formation Relative to T Cell-APC Conjugation J. Exp. Med., October 11, 2004; (2004) jem.20040780. [Abstract] [Full Text] [PDF]
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J. N. Wu, M. S. Jordan, M. A. Silverman, E. J. Peterson, and G. A. Koretzky Differential Requirement for Adapter Proteins Src Homology 2 Domain-Containing Leukocyte Phosphoprotein of 76 kDa and Adhesion- and Degranulation-Promoting Adapter Protein in Fc{epsilon}RI Signaling and Mast Cell Function J. Immunol., June 1, 2004; 172(11): 6768 - 6774. [Abstract] [Full Text] [PDF]
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E. Janssen, M. Zhu, B. Craven, and W. Zhang Linker for Activation of B Cells: A Functional Equivalent of a Mutant Linker for Activation of T Cells Deficient in Phospholipase C-{gamma}1 Binding J. Immunol., June 1, 2004; 172(11): 6810 - 6819. [Abstract] [Full Text] [PDF]
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S. Koonpaew, E. Janssen, M. Zhu, and W. Zhang The Importance of Three Membrane-distal Tyrosines in the Adaptor Protein NTAL/LAB J. Biol. Chem., March 19, 2004; 279(12): 11229 - 11235. [Abstract] [Full Text] [PDF]
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K. E. Nichols, K. Haines, P. S. Myung, S. Newbrough, E. Myers, H. Jumaa, D. J. Shedlock, H. Shen, and G. A. Koretzky Macrophage activation and Fc{gamma} receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors J. Leukoc. Biol., March 1, 2004; 75(3): 541 - 552. [Abstract] [Full Text] [PDF]
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E. M. Hur, M. Son, O.-H. Lee, Y. B. Choi, C. Park, H. Lee, and Y. Yun LIME, a Novel Transmembrane Adaptor Protein, Associates with p56lck and Mediates T Cell Activation J. Exp. Med., November 10, 2003; (2003) 20030232. [Abstract] [Full Text] [PDF]
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S. Sanzone, M. Zeyda, M. D. Saemann, M. Soncini, W. Holter, G. Fritsch, W. Knapp, F. Candotti, T. M. Stulnig, and O. Parolini SLAM-associated Protein Deficiency Causes Imbalanced Early Signal Transduction and Blocks Downstream Activation in T Cells from X-linked Lymphoproliferative Disease Patients J. Biol. Chem., August 8, 2003; 278(32): 29593 - 29599. [Abstract] [Full Text] [PDF]
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K. N. Kremer, T. D. Humphreys, A. Kumar, N.-X. Qian, and K. E. Hedin Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1{alpha}/CXCL12 Chemokine J. Immunol., July 1, 2003; 171(1): 360 - 367. [Abstract] [Full Text] [PDF]
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K. M. Dennehy, A. Kerstan, A. Bischof, J.-H. Park, S.-Y. Na, and T. Hunig Mitogenic signals through CD28 activate the protein kinase C{theta}-NF-{kappa}B pathway in primary peripheral T cells Int. Immunol., May 1, 2003; 15(5): 655 - 663. [Abstract] [Full Text] [PDF]
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M.-A. Kang, S.-Y. Yun, and J. Won Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity Blood, May 1, 2003; 101(9): 3534 - 3542. [Abstract] [Full Text] [PDF]
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A. Kettner, V. Pivniouk, L. Kumar, H. Falet, J.-S. Lee, R. Mulligan, and R. S. Geha Structural Requirements of SLP-76 in Signaling via the High-Affinity Immunoglobulin E Receptor (Fc{varepsilon}RI) in Mast Cells Mol. Cell. Biol., April 1, 2003; 23(7): 2395 - 2406. [Abstract] [Full Text] [PDF]
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M. Zhu, E. Janssen, and W. Zhang Minimal Requirement of Tyrosine Residues of Linker for Activation of T Cells in TCR Signaling and Thymocyte Development J. Immunol., January 1, 2003; 170(1): 325 - 333. [Abstract] [Full Text] [PDF]
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M. Zhu, E. Janssen, K. Leung, and W. Zhang Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling J. Biol. Chem., November 22, 2002; 277(48): 46151 - 46158. [Abstract] [Full Text] [PDF]
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S. C. Bunnell, D. I. Hong, J. R. Kardon, T. Yamazaki, C. J. McGlade, V. A. Barr, and L. E. Samelson T cell receptor ligation induces the formation of dynamically regulated signaling assemblies J. Cell Biol., September 29, 2002; 158(7): 1263 - 1275. [Abstract] [Full Text] [PDF]
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M. Zeyda, G. Staffler, V. Horejsi, W. Waldhausl, and T. M. Stulnig LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids J. Biol. Chem., August 2, 2002; 277(32): 28418 - 28423. [Abstract] [Full Text] [PDF]
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 M. Iwashima, M. Takamatsu, H. Yamagishi, Y. Hatanaka, Y.-Y. Huang, C. McGinty, S. Yamasaki, and T. Koike Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression PNAS, April 2, 2002; 99(7): 4544 - 4549. [Abstract] [Full Text] [PDF]
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A. E. Schade and A. D. Levine Lipid Raft Heterogeneity in Human Peripheral Blood T Lymphoblasts: A Mechanism for Regulating the Initiation of TCR Signal Transduction J. Immunol., March 1, 2002; 168(5): 2233 - 2239. [Abstract] [Full Text] [PDF]
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E. Teixeiro, P. Fuentes, B. Galocha, B. Alarcon, and R. Bragado T Cell Receptor-mediated Signal Transduction Controlled by the beta Chain Transmembrane Domain. APOPTOSIS-DEFICIENT CELLS DISPLAY UNBALANCED MITOGEN-ACTIVATED PROTEIN KINASES ACTIVITIES UPON T CELL RECEPTOR ENGAGEMENT J. Biol. Chem., February 1, 2002; 277(6): 3993 - 4002. [Abstract] [Full Text] [PDF]
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S. I. Gringhuis, E. A. M. Papendrecht-van der Voort, A. Leow, E. W. N. Levarht, F. C. Breedveld, and C. L. Verweij Effect of Redox Balance Alterations on Cellular Localization of LAT and Downstream T-Cell Receptor Signaling Pathways Mol. Cell. Biol., January 15, 2002; 22(2): 400 - 411. [Abstract] [Full Text] [PDF]
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S. S. Chuang, P. R. Kumaresan, and P. A. Mathew 2B4 (CD244)-Mediated Activation of Cytotoxicity and IFN-{gamma} Release in Human NK Cells Involves Distinct Pathways J. Immunol., December 1, 2001; 167(11): 6210 - 6216. [Abstract] [Full Text] [PDF]
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M. P. Martelli, J. Boomer, M. Bu, and B. E. Bierer T Cell Regulation of p62dok (Dok1) Association with Crk-L J. Biol. Chem., November 30, 2001; 276(49): 45654 - 45661. [Abstract] [Full Text] [PDF]
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X. Shan, R. Balakir, G. Criado, J. S. Wood, M.-C. Seminario, J. Madrenas, and R. L. Wange ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation Mol. Cell. Biol., November 1, 2001; 21(21): 7137 - 7149. [Abstract] [Full Text] [PDF]
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M.-C. Veri, K. E. DeBell, M.-C. Seminario, A. DiBaldassarre, I. Reischl, R. Rawat, L. Graham, C. Noviello, B. L. Rellahan, S. Miscia, et al. Membrane Raft-Dependent Regulation of Phospholipase C{gamma}-1 Activation in T Lymphocytes Mol. Cell. Biol., October 15, 2001; 21(20): 6939 - 6950. [Abstract] [Full Text] [PDF]
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C. L. Sommers, R. K. Menon, A. Grinberg, W. Zhang, L. E. Samelson, and P. E. Love Knock-in Mutation of the Distal Four Tyrosines of Linker for Activation of T Cells Blocks Murine T Cell Development J. Exp. Med., July 16, 2001; 194(2): 135 - 142. [Abstract] [Full Text] [PDF]
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D. Yablonski, T. Kadlecek, and A. Weiss Identification of a Phospholipase C-{gamma}1 (PLC-{gamma}1) SH3 Domain-Binding Site in SLP-76 Required for T-Cell Receptor-Mediated Activation of PLC-{gamma}1 and NFAT Mol. Cell. Biol., July 1, 2001; 21(13): 4208 - 4218. [Abstract] [Full Text] [PDF]
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T. M. Herndon, X. C. Shan, G. C. Tsokos, and R. L. Wange ZAP-70 and SLP-76 Regulate Protein Kinase C-{{theta}} and NF-{{kappa}}B Activation in Response to Engagement of CD3 and CD28 J. Immunol., May 1, 2001; 166(9): 5654 - 5664. [Abstract] [Full Text] [PDF]
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J. Dietrich, M. Cella, and M. Colonna Ig-Like Transcript 2 (ILT2)/Leukocyte Ig-Like Receptor 1 (LIR1) Inhibits TCR Signaling and Actin Cytoskeleton Reorganization J. Immunol., February 15, 2001; 166(4): 2514 - 2521. [Abstract] [Full Text] [PDF]
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B. J. Irvin, B. L. Williams, A. E. Nilson, H. O. Maynor, and R. T. Abraham Pleiotropic Contributions of Phospholipase C-gamma 1 (PLC-gamma 1) to T-Cell Antigen Receptor-Mediated Signaling: Reconstitution Studies of a PLC-gamma 1-Deficient Jurkat T-Cell Line Mol. Cell. Biol., December 15, 2000; 20(24): 9149 - 9161. [Abstract] [Full Text]
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T. Harder and M. Kuhn Selective Accumulation of Raft-Associated Membrane Protein Lat in T Cell Receptor Signaling Assemblies J. Cell Biol., October 16, 2000; 151(2): 199 - 208. [Abstract] [Full Text] [PDF]
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N. J. Boerth, J. J. Sadler, D. E. Bauer, J. L. Clements, S. M. Gheith, and G. A. Koretzky Recruitment of Slp-76 to the Membrane and Glycolipid-Enriched Membrane Microdomains Replaces the Requirement for Linker for Activation of T Cells in T Cell Receptor Signaling J. Exp. Med., October 2, 2000; 192(7): 1047 - 1058. [Abstract] [Full Text] [PDF]
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M. Ishiai, M. Kurosaki, K. Inabe, A. C. Chan, K. Sugamura, and T. Kurosaki Involvement of Lat, Gads, and Grb2 in Compartmentation of Slp-76 to the Plasma Membrane J. Exp. Med., September 18, 2000; 192(6): 847 - 856. [Abstract] [Full Text] [PDF]
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V. Sundvold, K. M. Torgersen, N. H. Post, F. Marti, P. D. King, J. A. Rottingen, A. Spurkland, and T. Lea Cutting Edge: T Cell-Specific Adapter Protein Inhibits T Cell Activation by Modulating Lck Activity J. Immunol., September 15, 2000; 165(6): 2927 - 2931. [Abstract] [Full Text] [PDF]
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M. P. Martelli, H. Lin, W. Zhang, L. E. Samelson, and B. E. Bierer Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation Blood, September 15, 2000; 96(6): 2181 - 2190. [Abstract] [Full Text] [PDF]
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R. J. Petrie, P. P. M. Schnetkamp, K. D. Patel, M. Awasthi-Kalia, and J. P. Deans Transient Translocation of the B Cell Receptor and Src Homology 2 Domain-Containing Inositol Phosphatase to Lipid Rafts: Evidence Toward a Role in Calcium Regulation J. Immunol., August 1, 2000; 165(3): 1220 - 1227. [Abstract] [Full Text] [PDF]
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A. Tamir, M. D. Eisenbraun, G. G. Garcia, and R. A. Miller Age-Dependent Alterations in the Assembly of Signal Transduction Complexes at the Site of T Cell/APC Interaction J. Immunol., August 1, 2000; 165(3): 1243 - 1251. [Abstract] [Full Text] [PDF]
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S. K. Liu, C. A. Smith, R. Arnold, F. Kiefer, and C. J. McGlade The Adaptor Protein Gads (Grb2-Related Adaptor Downstream of Shc) Is Implicated in Coupling Hemopoietic Progenitor Kinase-1 to the Activated TCR J. Immunol., August 1, 2000; 165(3): 1417 - 1426. [Abstract] [Full Text] [PDF]
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M. D. Eisenbraun, A. Tamir, and R. A. Miller Altered Composition of the Immunological Synapse in an Anergic, Age-Dependent Memory T Cell Subset J. Immunol., June 15, 2000; 164(12): 6105 - 6112. [Abstract] [Full Text] [PDF]
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E. E. Prieschl, R. Csonga, V. Novotny, G. E. Kikuchi, and T. Baumruker Glycosphingolipid-Induced Relocation of Lyn and Syk into Detergent-Resistant Membranes Results in Mast Cell Activation J. Immunol., May 15, 2000; 164(10): 5389 - 5397. [Abstract] [Full Text] [PDF]
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D. Peters, M. Tsuchida, E. R. Manthei, T. Alam, C. S. Cho, S. J. Knechtle, and M. M. Hamawy Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506 Blood, May 1, 2000; 95(9): 2733 - 2741. [Abstract] [Full Text] [PDF]
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S. Lemay, D. Davidson, S. Latour, and A. Veillette Dok-3, a Novel Adapter Molecule Involved in the Negative Regulation of Immunoreceptor Signaling Mol. Cell. Biol., April 15, 2000; 20(8): 2743 - 2754. [Abstract] [Full Text]
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R. Goitsuka, H. Kanazashi, H. Sasanuma, Y.-i. Fujimura, Y. Hidaka, A. Tatsuno, C. Ra, K. Hayashi, and D. Kitamura A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation Int. Immunol., April 1, 2000; 12(4): 573 - 580. [Abstract] [Full Text] [PDF]
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X. R. Bustelo Regulatory and Signaling Properties of the Vav Family Mol. Cell. Biol., March 1, 2000; 20(5): 1461 - 1477. [Full Text]
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K. V. Salojin, J. Zhang, C. Meagher, and T. L. Delovitch ZAP-70 Is Essential for the T Cell Antigen Receptor-induced Plasma Membrane Targeting of SOS and Vav in T Cells J. Biol. Chem., February 25, 2000; 275(8): 5966 - 5975. [Abstract] [Full Text] [PDF]
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S. C. Bunnell, M. Diehn, M. B. Yaffe, P. R. Findell, L. C. Cantley, and L. J. Berg Biochemical Interactions Integrating Itk with the T Cell Receptor-initiated Signaling Cascade J. Biol. Chem., January 21, 2000; 275(3): 2219 - 2230. [Abstract] [Full Text] [PDF]
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W. Zhang, R. P. Trible, M. Zhu, S. K. Liu, C. J. McGlade, and L. E. Samelson Association of Grb2, Gads, and Phospholipase C-gamma 1 with Phosphorylated LAT Tyrosine Residues. EFFECT OF LAT TYROSINE MUTATIONS ON T CELL ANTIGEN RECEPTOR-MEDIATED SIGNALING J. Biol. Chem., July 21, 2000; 275(30): 23355 - 23361. [Abstract] [Full Text] [PDF]
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J. Lin and A. Weiss Identification of the Minimal Tyrosine Residues Required for Linker for Activation of T Cell Function J. Biol. Chem., July 27, 2001; 276(31): 29588 - 29595. [Abstract] [Full Text] [PDF]
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R. Goitsuka, A. Tatsuno, M. Ishiai, T. Kurosaki, and D. Kitamura MIST Functions through Distinct Domains in Immunoreceptor Signaling in the Presence and Absence of LAT J. Biol. Chem., September 14, 2001; 276(38): 36043 - 36050. [Abstract] [Full Text] [PDF]
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M. Zubiaur, O. Fernandez, E. Ferrero, J. Salmeron, B. Malissen, F. Malavasi, and J. Sancho CD38 Is Associated with Lipid Rafts and upon Receptor Stimulation Leads to Akt/Protein Kinase B and Erk Activation in the Absence of the CD3-zeta Immune Receptor Tyrosine-based Activation Motifs J. Biol. Chem., January 4, 2002; 277(1): 13 - 22. [Abstract] [Full Text] [PDF]
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S. Tridandapani, T. W. Lyden, J. L. Smith, J. E. Carter, K. M. Coggeshall, and C. L. Anderson The Adapter Protein LAT Enhances Fcgamma Receptor-mediated Signal Transduction in Myeloid Cells J. Biol. Chem., June 30, 2000; 275(27): 20480 - 20487. [Abstract] [Full Text] [PDF]
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M. Iwashima, M. Takamatsu, H. Yamagishi, Y. Hatanaka, Y.-Y. Huang, C. McGinty, S. Yamasaki, and T. Koike Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression PNAS, April 2, 2002; 99(7): 4544 - 4549. [Abstract] [Full Text] [PDF]
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