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

---

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

Biological activities of the matrix glycoprotein thrombospondin-1 (TSP1) are cell type specific and depend on the relative expression or activation of several TSP1 receptors. Although engaging individual TSP1 receptors in T lymphocytes can elicit costimulating signals, in this study we show that intact TSP1 inhibits TCR-mediated T cell activation, assessed globally using cDNA microarrays. TSP1 signaling suppressed expression of several genes induced in Jurkat T cells, including the T cell activation markers CD69, early growth response gene-1 (Egr-1), and phosphatase of activated cells (PAC-1). TCR-stimulated and CD47-costimulated IL-2 secretion and cell surface CD69 expression were also inhibited by TSP1. The specific inhibitory effect of TSP1 was verified in freshly isolated human PBMCs. TSP1 inhibited TCR-mediated but not protein kinase C-mediated T cell activation. Using CD69 expression as a marker, we demonstrated that the inhibitory activity of TSP1 depended on two TSP1 receptors, CD47 and integrin-associated protein heparan sulfate proteoglycans. Signals from these receptors inhibited TCR signaling downstream of ZAP70, but upstream of NF-AT. Therefore, the expression of TSP1 induced during wound repair and in tumor stroma may limit T cell activation at these sites.
...
PMID:Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation. 1116 Mar 2

Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) is a receptor, specific for MHC class I molecules, that inhibits lymphoid and myeloid cells. Here, we analyzed the molecular and cellular mechanisms by which ILT2 modulates T cell activation in primary CTLs and transfected T cell lines. We found that cross-linking with the TCR and the activity of Src tyrosine kinase p56(lck) were required for phosphorylation of ILT2 and subsequent recruitment of Src homology protein 1. In contrast, ILT2 triggering resulted in reduced phosphorylation of TCRzeta and linker for activation of T cells, which led to reduced TCRzeta-ZAP70 complex formation, as well as extracellular signal-related kinase 1 and 2 activation. Furthermore, ILT2 inhibited both superantigen and anti-TCR Ab-induced rearrangement of the actin cytoskeleton. The inhibitory effect mediated by ILT2 is probably concentrated at the APC-T cell interface because both TCR and ILT2 were strongly polarized toward the APC upon engagement by their specific ligands. Thus, ILT2 inhibits both signaling and cellular events involved in the activation of T cells.
...
PMID:Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. 1116 Mar 12

Polyomavirus (PyV) infection induces protective T-cell-independent (TI) IgM and IgG responses in T-cell-deficient (TCR beta x delta-/-) mice. In this study, we show that PyV is a TI -2 antigen: B cells with a mutated Bruton's tyrosine kinase (Xid mutants) do not respond to PyV with antibody secretion in the absence of T cells. We also demonstrate that NK-cell-mediated "help" is not absolutely required for the induction of the TI-2 antibodies to PyV; thus for the first time, we provide evidence for protective IgM and IgG responses against a viral infection induced in mice lacking T and NK cells (CD3Etg). Comparison of the antibody responses observed in T- and NK-cell-deficient mice with those of mice lacking only T cells, however, suggests that NK cells may promote isotype switching to IgG2a. This effect is probably mediated by IFN gamma secretion. In support of this idea, studies on the antibody responses of PyV-infected SCID mice that had been reconstituted with IFN gamma R-/- B cells or wild-type B cells demonstrated the IFN gamma dependence of PyV-specific TI IgG2a secretion and provided evidence that IFN gamma acting directly on B cells plays an important role in TI pathways of isotype switching to IgG2a in vivo.
...
PMID:Antiviral T-cell-independent type 2 antibody responses induced in vivo in the absence of T and NK cells. 1116 30

The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation. Here, we investigated how CD28 costimulation functions to allow TCR-triggered resting T cells to acquire IL-12 responsiveness. When T cells are stimulated with low doses of anti-CD3 mAb, CD28 costimulation was required for the optimal levels of IL-12 receptor (IL-12R) expression. However, stimulation of T cells with high doses of anti-CD3 alone induced comparable levels of IL-12R expression to those induced upon CD28 costimulation. Nevertheless, there was a substantial difference in IL-12 responsiveness between these two groups of T cells: compared to anti-CD28-costimulated T cells, T cells that were not costimulated with anti-CD28 exhibited decreased levels of Janus kinases (JAK) JAK2/TYK2 and STAT4 phosphorylation and IFN-y production following IL-12 stimulation. Importantly, STAT6 phosphorylation following IL-4 stimulation was not decreased in anti-CD28-uncostimulated T cells. These resutls indicate that CD28 costimulation not only contributes to up-regulating IL-12R expression but is also required to render JAKs/STAT4 responsive to IL-12 stimulation.
...
PMID:CD28 costimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells. 1146 2

HIV-1 infection leads to T cell dysfunction and apoptosis in vivo and in vitro. The shared common gamma chain of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function and survival. We have reported that CD4 ligation with HIV gp120 inhibits T cell receptor-induced activation and expression of JAK3. We have also shown that while some strains of HIV-1, such as NL4-3, induce apoptosis of infected CD4(+) T cells, other strains, such as HIV-1 IIIB, do not. Interestingly, we show here that infection of CD4(+) T cells with HIV-1 NL4-3, but not IIIB, inhibited activation and expression of JAK3. NL4-3-infected T cells were unable to upregulate JAK3 expression following stimulation through TCR/CD3. In addition, NL4-3, but not IIIB, inhibited tyrosine phosphorylation and expression of STAT5, a downstream target of JAK3. These data suggest a correlation between apoptosis of HIV-1-infected T cells and inhibition of the JAK3/STAT5 activation pathway.
...
PMID:HIV-1 NL4-3, but not IIIB, inhibits JAK3/STAT5 activation in CD4(+) T cells. 1148 9

We report a physical and functional association between the Tec-family tyrosine kinase Itk (Emt/Tsk) and the nuclear import chaperone karyopherin alpha (Rch1alpha) in human T cells. The Itk-SH3 domain and the Rch1alpha proline-rich (PR) motif were crucial for the Itk/Rch1alpha constitutive interaction as demonstrated by directed mutagenesis of the Rch1alpha PR motif (proline 242 to alanine, P242A). TCR-CD3 stimulation of Jurkat T cells resulted in increased Itk/Rch1alpha complex formation, recruitment of karyopherin beta to the protein complex and Rch1alpha tyrosine phosphorylation. Analysis of in vitro kinase reactions with a panel of recombinant glutathione-S-transferase (GST) fusion tyrosine kinases (Itk, Lck, ZAP-70 and Jak3) revealed that only GST-Itk efficiently phosphorylated a recombinant GST-Rch1alpha fusion. We observed constitutive nuclear localization of Itk that was up-regulated following either TCR-CD3 stimulation or over-expression of wild-type Rch1alpha in T cells. Further, nuclear localization of Itk and TCR-CD3-mediated IL-2 production were significantly down-regulated following expression of the Rch1alpha-P242A mutant, implicating a role for Rch1alpha in the nuclear translocation of Itk.
...
PMID:Nuclear localization of the tyrosine kinase Itk and interaction of its SH3 domain with karyopherin alpha (Rch1alpha). 1158 Nov 71

CD28 provides a costimulatory signal that cooperates with the TCR/CD3 complex to induce T cell activation, cytokine production, and clonal expansion. We have recently shown that CD28 directly regulates progression of T lymphocytes through the cell cycle. Although a number of signaling pathways have been linked to the TCR/CD3 and to CD28, it is not known how these two receptors cooperate to induce cell cycle progression. Here, using cell-permeable pharmacologic inhibitors of phosphatidylinositol 3-hydroxykinase (PI3K) and mitogen-activated protein kinase kinase (MEK1/2), we show that cell cycle progression of primary T lymphocytes requires simultaneous activation of PI3K- and MEK1/2-dependent pathways. Decreased abundance of cyclin-dependent kinase inhibitor p27(kip1), which requires simultaneous TCR/CD3 and CD28 ligation, was dependent upon both MEK and PI3K activity. Ligation of TCR/CD3, but not CD28 alone, resulted in activation of MEK targets extracellular signal-related kinase 1/2, whereas ligation of CD28 alone was sufficient for activation of PI3K target protein kinase B (PKB; c-Akt). CD28 ligation alone was also sufficient to mediate inactivating phosphorylation of PKB target glycogen synthase kinase-3 (GSK-3). Moreover, direct inactivation of GSK-3 by LiCl in the presence of anti-CD3, but not in the presence of anti-CD28, resulted in down-regulation of p27(kip1), hyperphosphorylation of retinoblastoma tumor suppressor gene product, and cellular proliferation. Thus, inactivation of the PI3K-PKB target GSK-3 could substitute for CD28 but not for CD3 signals. These results show that the PI3K-PKB pathway links CD28 to cell cycle progression and suggest that p27(kip1) integrates mitogenic MEK- and PI3K-dependent signals from TCR and CD28 in primary T lymphocytes.
...
PMID:CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells. 1188 39

T-cell biological responses appear to involve the complex interaction of T-cell surface receptors, intracellular signaling molecules and the cytoskeleton. Both the serine/threonine protein kinase families protein kinase C (PKC) and protein kinase B or RAC-PK (AKT/PKB) have been implicated in signal transmission leading to activation, differentiation as well as cellular survival of T-lymphocytes. The PKC gene family consists of nine diverse isotypes (PKC alpha, beta, gamma, delta, epsilon, xi, eta, theta; and iota), the AKT/PKB gene family includes three kinases (AKT1/PKB alpha, AKT2/PKB beta, AKT3/PKB gamma). Here, we attempt to summarize the regulation as well as downstream signaling pathways of PKC and AKT/PKB isotypes, that may act additive in TCR/CD28 induced proliferation and survival of peripheral CD4+ T-lymphocytes.
...
PMID:Protein kinase C and AKT/protein kinase B in CD4+ T-lymphocytes: new partners in TCR/CD28 signal integration. 1204 76

Tumor necrosis factor (TNF)-alpha and lymphotoxin (LT) alpha/beta play multiple roles in the development and function of the immune system. This article focuses on three important aspects of the effects of these cytokines on the immune response and on autoimmunity. In several experimental systems (Jurkat T cells, murine T-cell hybridomas), TNF-alpha appears to cause a downregulation of signaling through the TCR, revealed by changes in calcium flux, activation of p21, p23 and ZAP70, and a decrease in nuclear activation of NF-kappaB. Previous and present results suggest that TNF-alpha interferes in some manner with signaling through the TCR, at a locus yet to be delineated. Transgenic expression of LTbetaR-Fc in nonobese diabetic (NOD) transgenic mice results in prevention of type 1 diabetes in NOD mice as long as the level of expression of the fusion protein (under the control of the cytomegalovirus promoter) remains above a level of 2-3 microg/ml. Once the expression levels of the fusion protein have dropped below this critical level, the diabetic process resumes and the animals become diabetic at 40-50 weeks of age, whereas nontransgenic littermates develop diabetes by 25-30 weeks of age. The paradoxical effects of neonatal TNF-alpha administration in NOD mice in increasing incidence of and hastening onset of type 1 diabetes, while neonatal anti-TNF administration completely prevents all signs of islet cell autoimmunity, are due partly to the low levels of CD4+CD25+ T cells in NOD mice. These low levels are reduced by a further 50% on neonatal administration of nontoxic levels of TNF-alpha. In contrast, neonatal administration of anti-TNF-alpha results in a dramatic increase in the levels of CD4+CD25+ regulatory T cells, to levels beyond those seen in wild-type untreated NOD mice. TNF-alpha and LTalpha/beta thus have pleomorphic regulatory effects on the development and expression of autoimmunity.
...
PMID:Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunity. 1211 Jan 33

Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): "conventional," TCR signaling-dependent costimulatory mAbs and "superagonistic" mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C"D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C"D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C"D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor kappaB pathway without inducing phosphorylation of either TCRzeta or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs.
...
PMID:Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. 1270 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---