Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell and B-cell antigen receptors are representative of a family of multisubunit receptors that utilize Src-family kinases as proximal cytoplasmic effectors in signal transduction. Recent studies have shown that distinct receptor subunits mediate ligand and effector interactions and demonstrate that physical interaction with effectors, and their activation, is a function of a 26 amino acid motif found in multiple receptor subunits. Further, receptor ligation induces tyrosine phosphorylation of this motif, and this initiates SH2-mediated association and activation of Src-family kinases and, apparently, ZAP70 kinases. Finally, this association triggers SH3-mediated binding of Lyn and Fyn to PI3-K, resulting in PI3-K activation. An integrated model of signal transduction is presented.
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PMID:The hetero-oligomeric antigen receptor complex and its coupling to cytoplasmic effectors. 819 41

In the present study, we investigated the developmental potential of purified populations of transitional CD4inCD8hi and CD4hiCD8in thymocytes that were further defined according to their differentiation stage by their levels of T cell receptor (TCR) expression into TCRlo, TCRin and TCRhi subpopulations. The differentiation potential of each of these subsets was tested in vitro in a single-cell suspension culture assay that showed that CD4inCD8hiTCRhi are precursors of CD8 single-positive cells, whereas CD4hiCD8inTCRin/hi are precursors of both CD4 and CD8 single-positive thymocytes. The analysis of transitional subsets in mutant mice for either beta 2-microglobulin or major histocompatibility complex (MHC) class II further revealed that lineage commitment to the CD8 lineage requires a TCR-MHC class I engagement, presumably at the immature double-positive stage of thymic development, while CD4 commitment does not require an MHC class II-mediated signal, but rather occurs by default. Using the addition of MHC class I- or class II-expressing cells or the addition of total thymocytes to purified sorted transitional precursors for the duration of the cultures in vitro, we identified an additional stage of differentiation for both CD4 and CD8 lineages that requires a positive selection signal. Examination of protein tyrosine phosphorylation of transitional precursors revealed that CD4inCD8hi transitional cells contain a high level of a 70-kDa phosphorylated protein consistent with a role for ZAP70 in the signal transduction during the positive selection of CD8+ cells.
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PMID:CD8/CD4 lineage commitment occurs by an instructional/default process followed by positive selection. 861 19

The fate of developing CD4+CD8+ thymocytes is determined by signals transduced through surface TCR complexes. Here, we report that cross-linking of TCR on CD4+ CD8+ thymocytes fails to activate ZAP70 protein tyrosine kinase and fails to initiate downstream signaling events, unless the TCR are coaggregated with surface coreceptor molecules. TCR signaling in CD4+CD8+ thymocytes is impaired because the number of available p56lck molecules is diminished by intrathymic CD4-Ia interactions that initially activate p56lck molecules, which are subsequently degraded. As a consequence of intrathymic CD4-Ia interactions, TCR zeta chains are initially phosphorylated to recruit ZAP70 molecules, but the recruited ZAP70 molecules are not subsequently phosphorylated, resulting in TCR complexes that are stably associated with inactive ZAP70 molecules. Thus, intrathymic interactions that diminish p56lck regulate TCR signaling thresholds and affect TCR structure in developing CD4+CD8+ thymocytes.
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PMID:TCR activation of ZAP70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available p56lck. 863 Jul 34

The absence of CTLA-4 results in uncontrolled T cell proliferation. The T cell receptor-specific kinases FYN, LCK, and ZAP-70 as well as the RAS pathway were found to be activated in T cells of Ctla-4-/- mutant mice. In addition, CTLA-4 specifically associated with the tyrosine phosphatase SYP, an interaction mediated by the SRC homology 2 (SH2) domains of SYP and the phosphotyrosine sequence Tyr-Val-Lys-Met within the CTLA-4 cytoplasmic tail. The CTLA-4-associated SYP had phosphatase activity toward the RAS regulator p52SHC. Thus, the RAS pathway and T cell activation through the T cell receptor are regulated by CTLA-4-associated SYP.
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PMID:Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. 863 61

The zeta polypeptide is part of the T cell antigen receptor (TCR). The zeta-chain contributes to efficient cell-surface expression of the TCR and accounts for part of its signal transduction capability. TCR recognition triggers a complex set of events that result in cellular activation. The protein tyrosine kinase (PTK) Lck phosphorylates the zeta-chain, which in turn associates with another PTK, ZAP70, and stimulates its phosphorylation activity. Here we report the expression of the intracellular part of the zeta-chain and its biochemical characterization. The recombinant protein does not dimerize by itself in solution. Circular-dichroic analysis reveals a random coil conformation. zeta, phosphorylated using recombinant Lck, associates with recombinant ZAP70 tandem-SH2 domains. All three T cell activation motifs in zeta bind ZAP70 tandem-SH2 domains in vitro, forming a 1:3 complex. This result extends the picture, derived from earlier studies, of a mechanism for signal amplification.
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PMID:Phosphorylated T cell receptor zeta-chain and ZAP70 tandem SH2 domains form a 1:3 complex in vitro. 868 56

The recognition that defects of ZAP-70 and, more recently, of JAK3 kinase in humans result in severe combined immunodeficiency, and the demonstration that targeting of these and other protein-kinase genes in mice also leads to immunodeficiency, have highlighted the crucial role that these proteins play in T-cell differentiation and activation.
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PMID:Immunodeficiencies caused by genetic defects in protein kinases. 879 5

Methodology has been developed which gives a specific measure of the interaction of an SH2 domain with a phosphopeptide ligand using scintillation proximity assay (SPA) technology. Recombinant SH2 domains were expressed from a T7 RNA polymerase-based vector in Escherichia coli as fusions to the C-terminus of the FK506-binding protein (FKBP) and purified from freeze-thaw lysates in high yield by affinity chromatography using immobilized phosphopeptides. For binding assays the phosphopeptide ligands were synthesized with a biotin tag and the FKBP fusion proteins were noncovalently radiolabeled with commercially available [3H]dihydroFK506. Complexes of tritiated SH2 fusion protein and biotinyl-phosphopeptide were then captured on streptavidin-coated SPA beads and counted. The modular protocol is an equilibrium technique that does not employ washing steps or specialized radiochemical syntheses required in other binding assays. The utility of the assay has been demonstrated in an examination of the ligand specificity of the SH2 domains of the tyrosine kinases ZAP70, Syk, and Lck. The methodology is potentially generalizable to any receptor-ligand interaction in which one component can be expressed as a fusion partner with FKBP and the other component can be captured on a SPA bead.
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PMID:The utility of FK506-binding protein as a fusion partner in scintillation proximity assays: application to SH2 domains. 881 23

Regulation through phosphorylation is a characteristic of signalling pathways and the lymphocyte kinase Lck (p56lck) both performs phosphorylation and is affected by it. Lck is a Src-family tyrosine kinase expressed in T lymphocytes, where it participates in the cellular immune response. Like all Src homologues, it comprises SH3, SH2 and kinase domains. Lck associates through its distinctive amino-terminal segment with the cytoplasmic tails of either T-cell co-receptor, CD4 or CD8-alpha. Activated Lck phosphorylates T-cell receptor zeta-chains, which then recruit the ZAP70 kinase to promote T-cell activation. Lck is activated by autophosphorylation at Tyr 394 in the activation loop and it is inactive when Tyr 505 near the carboxy terminus is phosphorylated and interacts with its own SH2 domain. Here we report the crystal structure of the Lck tyrosine kinase domain (LCKK) in its activated state at 1.7 A resolution. The structure reveals how a phosphoryl group at Tyr 394 generates a competent active site. Comparisons with other kinase structures indicate that tyrosine phophophorylation and ligand binding may in general elicit two distinct hinge-like movements between the kinase subdomains. From modelling studies, we suggest a basis for inhibition by phosphorylation at Tyr 505.
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PMID:Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. 894 79

The chemokine RANTES is a chemoattractant and activating factor for T lymphocytes. Investigation of the signal transduction mechanisms induced by RANTES in T cells revealed tyrosine phosphorylation of multiple protein species with prominent bands at 70-85 and 120-130 kD. Immunoprecipitation and Western analyses revealed that a protein of 125 kD was identical to the focal adhesion kinase (FAK) pp125FAK. RANTES stimulated phosphorylation of FAK as early as 30 seconds and immunoblots using antiphosphotyrosine monoclonal antibodies revealed that there was consistent phosphorylation of a 68-70 kD species in the pp125FAK immunoprecipitates. Immunoblotting and kinase assays showed this to be two separate proteins, the tyrosine kinase zeta-associated protein (ZAP) 70, and the focal adhesion protein paxillin. These results indicate a potentially important role for RANTES in the generation of T cell focal adhesions and subsequent cell activation via a molecular complex containing FAK, ZAP-70, and paxillin.
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PMID:RANTES induces tyrosine kinase activity of stably complexed p125FAK and ZAP-70 in human T cells. 906 47

The Src family protein tyrosine kinases (PTKs), Lck and Fyn, are coexpressed in T cells and perform crucial functions involved in the initiation of T cell antigen receptor (TCR) signal transduction. However, the mechanisms by which Lck and Fyn regulate TCR signaling are still not completely understood. One important question is whether Lck and Fyn have specific targets or only provide functional redundancy during TCR signaling. We have previously shown that Lck plays a major role in the tyrosine phosphorylation of the TCR-zeta chain and the ZAP-70 PTK. In an effort to identify the targets that are specifically regulated by Fyn, we have studied the tyrosine phosphorylation of Pyk2, a recently discovered new member of the focal adhesion kinase family PTK. We demonstrated that Pyk2 was rapidly tyrosine phosphorylated following TCR stimulation. TCR-induced tyrosine phosphorylation of Pyk2 was selectively dependent on Fyn but not Lck. Moreover, in heterologous COS-7 cells, coexpression of Pyk2 with Fyn but not Lck resulted in substantial increases in Pyk2 tyrosine phosphorylation. The selective regulation of Pyk2 tyrosine phosphorylation by Fyn in vivo correlated with the preferential phosphorylation of Pyk2 by Fyn in vitro. Our results demonstrate that Pyk2 is a specific target regulated by Fyn during TCR signaling.
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PMID:Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. 910 12


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