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)

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-zeta chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
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PMID:Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70. 936 25

Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells induces secretion of cytokines, including interleukin (IL)-2, through transcriptional activation of cytokine genes. Previously, defects in the gene coding for Bruton's tyrosine kinase (Btk) were shown to result in defective cytokine production in mast cells, and thereby mice carrying btk mutations exhibited diminished anaphylactic reactions in response to IgE and antigen. In this study, we provide evidence that the transcription factors involved in the IL-2 gene expression in T cells are also required for maximal activation of the IL-2 gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT were identified as candidate transcription factors that are regulated by Btk. Consistent with our previous data indicating that Btk regulates stress-activated protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable transcription factors are activated by FcepsilonRI cross-linking in a Btk-dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells.
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PMID:Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells. Dependence on the c-Jun N-terminal kinase activation pathway. 955 77

Binding of IL-2 to its receptor activates several biochemical pathways, but precisely how these pathways are linked is incompletely understood. Here, we report that SHP-2, an SH2-domain containing tyrosine phosphatase, associates with different molecules of the IL-2 signaling cascade. Upon IL-2 stimulation, SHP-2 was coimmunoprecipitated with Grb2 and the p85 subunit of phosphatidylinositol 3-kinase. In contrast, SHP-2 was constitutively associated with JAK1 and JAK3. Finally, SHP-2 expression amplified STAT-dependent transcriptional activation whereas a dominant negative allele inhibited transactivation and the IL-2-induced activation of MAPK (mitogen-activated protein kinase). These results demonstrate the involvement of SHP-2 in multiple pathways of the IL-2 signaling cascade and provide evidence for its positive regulatory role.
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PMID:Involvement of SHP-2 in multiple aspects of IL-2 signaling: evidence for a positive regulatory role. 959 Feb 9

In early HIV disease, immunodeficiency is characterized by the inability of CD4+ T cells to produce a critical cytokine, IL-2, and to express the receptor for IL-2 (IL-2R) in response to antigenic or mitogenic stimulation. The shared common gamma-chain (gamma(c)) of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function. Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3. Stimulation through the gamma(c)-related cytokine receptors restores JAK3 expression and activation and rescues CD4-mediated T cell unresponsiveness. Collectively, these data argue that inhibition of JAK3 expression and activation may, in part, explain the T cell dysfunction seen in early HIV disease. In addition, rescue from gp120-mediated T cell unresponsiveness by activation of JAK3 suggests a novel therapeutic approach for enhancing immune function in HIV disease.
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PMID:Cutting edge: JAK3 activation and rescue of T cells from HIV gp120-induced unresponsiveness. 963 77

IL-13, a cytokine similar to IL-4, is a regulator of human B cell and monocyte functions. Biologic effects of IL-13 on primary human NK and T cells have not been well defined. We demonstrate that, in primary NK cells, IL-13, but not IL-4, may induce low levels of IFN-gamma secretion. When NK cells were costimulated with IL-13 and IL-2, IL-13 generally resulted in two types of reactivity: IL-13 synergized with IL-2 to stimulate IFN-gamma production or it modestly inhibited IL-2-mediated IFN-gamma production. In both types of donors, the effect of IL-13 on IL-2-induced IFN-gamma production was in marked contrast to the strong inhibition seen with IL-4 in NK cells. Additionally, IL-13 suppresses IL-2-induced NK cytolytic and proliferative activities although less efficiently than IL-4. In T cells, IL-13 inhibits anti-CD3 mAb/IL-2- or PHA-mediated IFN-gamma production and enhances cytolytic potential. Furthermore, we demonstrate that IL-13, like IL-4, induces distinct STAT6-DNA binding complexes and tyrosine phosphorylation of STAT6 and Janus kinase 3 (JAK3) in NK and T cells. We observed that Abs directed against unique domains of STAT6 have differential effects on complexes in T cells but not in NK cells, suggesting different STAT6 isoforms. These findings show that IL-13 and IL-4 have the ability to regulate NK and T cell activation and that IL-13 is a potent regulator of STAT6 and JAK3 in these cell types.
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PMID:Differential regulation of the Janus kinase-STAT pathway and biologic function of IL-13 in primary human NK and T cells: a comparative study with IL-4. 964 27

Ligation of the CD2 co-stimulatory receptor on human T lymphocytes induces tyrosine phosphorylation and activation of the Tec-family tyrosine kinase, ITK. To examine whether any of several proline-rich (PR) stretches of the CD2 cytoplasmic tail are necessary for ITK activation we introduced wild-type and mutated versions of rat CD2, each missing at least one PR stretch of the tail, into human Jurkat T leukemia cells. The influence of cytoplasmic tail mutations was then studied following stimulation of transfectants with the rat CD2 mAb pair, OX54/OX55. As predicted, wild-type rat CD2 was able to activate ITK in Jurkat cells. In addition, a truncation mutant, lacking the most membrane-distal PR stretch, PR6, was able to activate ITK. By contrast, all other studied truncation mutants, each of which is missing at least PR4-PR6, were unable to induce ITK activation. Of deletion mutants, deletion of the membrane-proximal PR stretches, PR1-PR3, did not impair rat CD2-mediated ITK activation. However, additional deletion of PR4 from a tail missing PR1 and PR2, deletion of PR2 and PR4, and deletion of PR4 alone from rat CD2 abrogated an ability to activate ITK. Thus, these results identify PR4 as an element of the CD2 tail that is required for activation of ITK. Furthermore, we show that, unlike wild-type rat CD2, PR4-deleted rat CD2 is unable to induce IL-2 secretion from Jurkat cells. This is consistent with the view that PR4-mediated activation of ITK is important for downstream signaling events induced by CD2 co-stimulation.
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PMID:CD2-mediated activation of the Tec-family tyrosine kinase ITK is controlled by proline-rich stretch-4 of the CD2 cytoplasmic tail. 970 Oct 39

We examined the potential of generating an immune response against Philadelphia chromosome-positive acute lymphoblastic leukemia. The immunostimulatory molecules chosen for this study were the cytokines IL-2 and GM-CSF and the costimulatory ligand CD80 (B7.1). We used a murine model based on a BALB/c pre-B cell line, BM185wt, in which leukemia is induced by the p185 BCR-ABL oncogenic product, which reproduces Philadelphia chromosome-positive ALL. BM185wt cells were transduced with retroviral vectors and the transduced clones expressing mIL-2, mGM-CSF, or mCD80 were used for challenge. Expression of the immunomodulators by BM185 cells was correlated with delay in leukemia development in immunocompetent mice, but not in immunodeficient mice, indicating an immune response against the modified leukemia cells. Expression of CD80 caused leukemia rejection in 50% of the cohort, which was associated with the CD4+ and CD8+ T cell-dependent development of anti-leukemia cytotoxic T lymphocytes. Furthermore, mice surviving the BM185/CD80 challenge or preimmunized with irradiated BM185/CD80 cells developed an immune response against subsequent challenge with the parental leukemia. These studies provide evidence that immunotherapeutic approaches can be developed for the treatment of ALL.
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PMID:Immune response to Philadelphia chromosome-positive acute lymphoblastic leukemia induced by expression of CD80, interleukin 2, and granulocyte-macrophage colony-stimulating factor. 975 32

Cytokine pathways are essential for the differentiation and function of lymphoid cells. The major T-cell growth factor is IL-2, which is produced by subsets of T lymphocytes in response to antigenic stimulation. The IL-2 receptor is expressed by T cells after antigenic stimulation, and when engaged by IL-2 induces proliferation, differentiation, and protection from apoptosis. Rare patients with severe combined immune deficiency (SCID) have been found to have mature T lymphocytes that do not produce IL-2, although no genetic abnormality has yet been defined for these patients. The fact that these patients and IL-2 knockout mice have the ability to generate mature T lymphocytes indicates that IL-2 is the major growth factor for mature T lymphocytes but not for immature thymocytes. X-linked SCID, the most common form of SCID, has a phenotype of thymic hypoplasia, peripheral T lymphopenia, the presence of B lymphocytes that do not undergo normal class switching, and usually the absence of natural killer (NK) cells. X-SCID is caused by mutations of a receptor subunit, which was originally described as the IL-2Rgamma. The phenotypic differences between X-SCID and IL-2-deficient SCID suggests that the IL-2Rgamma chain might be a component of other receptors needed for thymic development, B cell class-switching, and NK development. The IL-2Rgamma is now known to be a shared subunit between the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, which explains the complex X-SCID phenotype. Because of this shared usage, the IL-2Rgamma is known as the common gamma chain (gamma c). Each ligand induces dimerization of gamma c with the ligand-specific receptor subunit, eg, the IL-2Rbeta, resulting in signal transduction through the JAK-STAT (signal transducers and activators of transcription) pathway. The JAK3 tyrosine kinase is constitutively associated with the gamma c and is necessary for signaling through the gamma c-containing receptors. Deficiency of JAK3 gives rise to a SCID phenotype that closely resembles that of X-SCID, but is autosomally recessive in inheritance. It is likely that other specific immune deficiencies of the cytokine pathways exist, eg, IL-7Ralpha-deficient SCID. T cells with wild-type gamma c and JAK3 proteins have a profound selective advantage over cells that contain mutant proteins. The selective advantage allows these patients to be treated by bone marrow transplantation (BMT) without ablative chemotherapy, and is the reason that these forms of SCID are potential targets for early gene therapy efforts.
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PMID:X-linked SCID and other defects of cytokine pathways. 980 Dec 59

Beta1 integrins can provide T cell co-stimulation, but little is known concerning their downstream signaling pathways. We found that Pyk2, a focal adhesion kinase-related tyrosine kinase, is regulated by beta1 integrin signaling in human T cells. Stimulation of Jurkat T cells with the alpha4beta1 integrin ligand VCAM-1 results in Pyk2 tyrosine phosphorylation, and combined stimulation with VCAM-1 and anti-CD3 mAb induces rapid and sustained synergistic Pyk2 phosphorylation. Studies with mAb suggest that in synergistic CD3- and alpha4beta1 integrin-mediated Pyk2 tyrosine phosphorylation, a major contribution of CD3-derived signals is independent of their effects on regulating integrin adhesion. Analysis of resting human CD4+ T cells confirmed the ability of CD3-derived signals to synergize with beta1 integrin-dependent signals in the induction of Pyk2 tyrosine phosphorylation. In addition, although CD28-mediated co-stimulatory signals were able to synergize with CD3-mediated signals in inducing ERK and JNK activation and secretion of IL-2 in the primary T cells, they did not contribute to the induction of Pyk2 phosphorylation. Taken together, these results indicate a potential role for Pyk2 in T cell co-stimulation mediated specifically by beta1 integrins.
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PMID:Pyk2 is differentially regulated by beta1 integrin- and CD28-mediated co-stimulation in human CD4+ T lymphocytes. 984 30

Severe combined immunodeficiency (SCID) is caused by multiple genetic defects. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor gamma chain (gamma(c)) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice and that Il/7r-deficient mice have NK cells, we hypothesized that T(-)B(+)NK(+) SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested. We now demonstrate that defective IL7R expression causes T(-)B(+)NK(+) SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling.
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PMID:Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. 984 16


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