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)

The cell surface molecules involved in the human cytolytic T lymphocyte (CTL)-synovial cell interaction may play an important role in T cell interactions with connective tissue mesenchymal cells. To examine the molecular basis for the CTL-synovial cell interaction, we immortalized synovial cell explants to establish the cell line SYN.SPP. The SYN.SPP cell line was compared to the established B lymphoblastoid cell line JY. Cell surface immunofluorescence demonstrated significantly different levels of the immunologically relevant cell surface molecules ICAM-1 and LFA-3. Both cell lines were used to stimulate CTL precursors. After several months in culture, CTL lines stimulated by the SYN.SPP and JY cell lines demonstrated HLA class I-directed cytolytic activity. The cell surface molecules utilized by the anti-SYN.SPP and anti-JY CTL lines were identified by monoclonal antibody (MAb) inhibition. MAb recognizing the CTL cell surface molecules CD3, CD8 and LFA-1 (CD11a) significantly inhibited CTL-mediated lysis of both target cells. An interesting observation was that the anti-SYN.SPP CTL line appeared to utilize the ICAM-1 and not the LFA-3 target cell molecule. In contrast, the anti-JY CTL line utilized the LFA-3 and not the ICAM-1 membrane molecule. These results indicate that CTL interactions with connective tissue mesenchymal cells may be regulated by a unique pattern of antigen nonspecific cell-cell interaction molecules.
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PMID:Intercellular adhesion molecule-1 (ICAM-1) is involved in the cytolytic T lymphocyte interaction with a human synovial cell line. 304 28

FAK, focal adhesion kinase, is expressed in a variety of cell types and has been suggested to transduce signals brought about by integrin-extracellular matrix (ECM) interactions. Integrin stimulation increases tyrosine phosphorylation and activity of FAK in all the cells examined to date. In contrast, in thymocytes stimulation of VLA-4 (alpha 4 beta 1) and LFA-1 (alpha L beta 2) resulted in a marked decrease in tyrosine phosphorylation and activity of FAK.
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PMID:Integrin stimulation decreases tyrosine phosphorylation and activity of focal adhesion kinase in thymocytes. 748 75

The basic tenet underlying the present work and supported by recent studies is that there is a dialogue between developing thymocytes and thymic stromal cells. One direction in this dialogue, i.e. thymic stromal cell role in shaping thymocyte maturation, has been extensively studied. The other direction, thymocyte effect on stromal cell development and function, started to emerge only recently on the basis of in vivo observations in SCID and knockout mice. An in vitro approach to the analysis of this interaction may add substantial insight into the process, as demonstrated by the present work. We made use of a culture system of either murine thymic epithelial cells (TEC line) cultured alone or cocultured with thymocytes. Unstimulated thymocytes or their supernatant caused 40-80% inhibition of TEC cell proliferation, as measured by 3H-thymidine incorporation. Cell cycle analysis by flow cytometry indicated that this inhibition can be attributed to reduction in G2/M phase cell number pari passu with an increase in Go/G1 cell number. This inhibitory effect was found to be partially mediated by TGF-beta produced by thymocytes. On the other hand, thymocytes augmented IL-6 production by TEC cells in coculture, an effect which could not be reproduced by thymocyte culture supernatant and was not inhibited by thymocyte pretreatment with formaldehyde or emetine. Furthermore, antibodies against thymocyte adhesion molecules (CD2, LFA-1) blocked the thymocyte-induced IL-6 secretion. IL-6 was found to be an autocrine growth factor of TEC in culture, since a combination of anti IL-6 and anti IL-6 receptor antibodies caused 70% inhibition of TEC proliferation and addition of exogenous recombinant IL-6 doubled the rate of proliferation. These results suggest that thymocytes regulate thymic epithelial cell growth by a complex set of inhibitory and enhancing signals mediated through either soluble factors or direct contact. The ultimate effect is dependent on the balance between different signals and may be different in different microenvironmental settings in vivo. In coculture in vitro the dominant effect was growth inhibition of the epithelial cells by thymocytes.
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PMID:The role of thymocytes in regulating thymic epithelial cell growth and function. 763 Nov 52

Mouse thymic epithelial cell lines (MTEC) were established from Day 14-18 fetal thymus by two novel protocols. The first protocol involved the selection of TEC by the formation of complexes with adult thymocytes after transformation with the helper-free Ad5.SVR4 recombinant virus. The second protocol involved the stimulation and selection of TEC in Ca(2+)-free medium by the formation of complexes with Day 14 fetal thymocytes. The resulting TECs formed several types of thymic epithelial clusters to which Day 14 fetal thymocytes could bind. Many of these fetal thymocytes could deeply infiltrate, colonize, and proliferate within the clusters of NCAM(high) LFA-1(low) TEC (MTSC-0420-1.4, MTSC-0420-1.5, and MTSC-0613-1.2 clusters), whereas very few could infiltrate the clusters of NCAM(low) LFA-1(high) TEC (MTSC-0531-5.1 and MTSC-0531-5.2) and none bound to or infiltrated an NCAM(neg) fibroblast cluster (MTSC-fibro.). Hence, it is possible that the NCAM-positive epithelial cell lines are derived from the thymus cortex, where they may play an important role in intrathymic migration and the clonal growth of pro-T cells in fetal thymus.
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PMID:Reproducible procedures for establishing mouse thymic stromal cell lines. 834 68

Signal transduction through integrin molecules expressed on platelets and nonlymphoid cells involves activation of the intracellular focal adhesion kinase ppI25FAK (FAK) to phosphorylate substrate proteins on tyrosine residues. Similar mechanisms are also functional in T-lymphocytes through the beta 1-integrin VLA-4. A putative FAK-related phosphoprotein (fakB) was identified that is responsive to intracellular signals induced through ligation of antigen receptors on both T- and B-lymphocytes, and whose induced tyrosine phosphorylation is augmented by TCR costimulation through the adhesion/costimulatory receptors CD2 and CD4. In this report, fakB is shown to respond to extracellular signals through the beta 2-integrin LFA-1 in the absence of primary signals through the TCR. Protein-protein complex formation was observed involving an association between fakB, phospholipase C gamma 1 (PLC gamma 1), and the tyrosine phosphoprotein pp35-36. Evidence is provided here that fakB interacts with PLC gamma 1 through its SH3 domain. The association between fakB and PLC gamma 1 does not appear to require T-cell activation, whereas the induced tyrosine phosphorylation of the protein complex components occurs following engagement of LFA-1. These data indicate that the beta2-integrin LFA-1 expressed on T-lymphocytes stimulates a novel, FAK-related molecule that may function in the interplay between adhesion receptors and intracellular signaling enzymes responsible for downstream second messenger generation.
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PMID:Focal adhesion kinase-related fakB is regulated by the integrin LFA-1 and interacts with the SH3 domain of phospholipase C gamma 1. 866 Aug 53

To elucidate the signaling mechanism of CD38 (a transmembrane molecule highly expressed in immature hemopoietic cells), we transfected Ba/F3 murine pro-B cells with a cDNA encoding human CD38. CD38 ligation with anti-CD38 Abs caused rapid, transient, dose-dependent tyrosine phosphorylation of several proteins, including the tyrosine kinase TEC and the adaptor molecule CBL, and association of tyrosine-phosphorylated proteins with phosphatidylinositol 3-kinase p85. Exposure to anti-CD38 Abs or their F(ab')2 and Fab also induced tight aggregation of CD38-transfected Ba/F3 cells, which appeared to be Ca2+ and Mg2+ independent and did not involved LFA-1. Aggregation was abrogated by addition of the tyrosine kinase inhibitor herbimycin A and was delayed by the phosphatidylinositol 3-kinase inhibitor wortmannin, suggesting a link between biochemical events and cellular effects induced by CD38. Cell aggregation was accompanied by a decrease in cell recovery. After 3 days of culture on bone marrow-derived stroma, the mean (+/-SD) cell recovery in the presence of anti-CD38 (T16) was 10.5 +/- 9.2% (n = 7) of that in parallel cultures with an isotype-matched nonreactive Ab. Finally, CD38 ligation in Ba/F3 cells expressing a mutant human CD38 lacking the cytoplasmic domain induced tyrosine phosphorylation with intensity and kinetics similar to those seen with the entire protein. It also induced cell aggregation and decreased cell recovery. We conclude that CD38 triggers remarkably similar signaling pathways in human and murine immature B cells. This signaling is independent of the CD38 cytoplasmic domain, suggesting the existence of accessory transmembrane molecules associated with CD38.
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PMID:CD38-mediated signaling events in murine pro-B cells expressing human CD38 with or without its cytoplasmic domain. 997 64

The locomotion of T lymphocytes within 3-D extracellular matrix (ECM) is a highly dynamic and flexible process following the principles of ameboid movement. Ameboid motility is characterized by a polarized yet simple cell shape allowing high speed, rapid directional oscillations, and low affinity interactions to the substrate that are coupled to a low degree of cytoskeletal organization lacking discrete focal contacts. At the onset of T cell migration, a default program, here described as migration-associated polarization, is initiated, resulting in the polar redistribution of cell surface receptors and cytoskeletal elements. Polarization involves protein cycling either to the leading edge (i.e. LFA-1, CD45RO, chemokine receptors, focal adhesion kinase), to a central polarizing compartment (MTOC, PKC, MARCKS), or into the uropod (CD44, CD43, ICAM-1 and -3, beta1 integrins). The function of such compartment formation may be important in chemotactic response, scanning of encountered cells, and a flexible and adaptive interaction with the ECM itself. Due to the simple shape and a diffusely organized cytoskeleton, the interactions to the surrounding extracellular matrix are rapid and reversible and appear to allow a broad spectrum of molecular migration strategies. These range from (1) adhesive and haptokinetic following i.e. chemokine-induced motility across 2-D surfaces to (2) largely integrin-independent migration predominantly guided by shape change and morphological flexibility, as seen in 3-D type I collagen matrices. Their prominent capacity to rapidly adapt to a given structural environment coupled to contact guidance mechanisms set T cell locomotion apart from slow, focal contact-dependent and more adhesive migration strategies established by fibroblast-like cells and cell clusters. It is therefore likely that, within the tissues, besides chemotactic or haptotactic gradients, the preformed matrix structure has an important impact on T cell trafficking and positioning in health and disease.
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PMID:T cell migration in three-dimensional extracellular matrix: guidance by polarity and sensations. 1109 16

Engagement of very late Ag-4 (integrin alpha(4)beta(1)) by ligands such as VCAM-1 markedly stimulates leukocyte migration mediated by LFA-1 (integrin alpha(L)beta(2)). This form of integrin trans-regulation in T cells requires the binding of paxillin to the alpha(4) integrin cytoplasmic domain. This conclusion is based on the abolition of trans-regulation in Jurkat T cells by an alpha(4) mutation (alpha(4)(Y991A)) that disrupts paxillin binding. Furthermore, cellular expression of an alpha(4)-binding fragment of paxillin that blocks the alpha(4)-paxillin interaction, selectively blocked VCAM-1 stimulation of alpha(L)beta(2)-dependent cell migration. The alpha(4)-paxillin association mediates trans-regulation by enhancing the activation of tyrosine kinases, focal adhesion kinase (FAK) and/or proline-rich tyrosine kinase-2 (Pyk2), based on two lines of evidence. First, disruption of the paxillin-binding site in the alpha(4) tail resulted in much less alpha(4)beta(1)-mediated phosphorylation of Pyk2 and FAK. Second, transfection with cDNAs encoding C-terminal fragments of Pyk2 and FAK, which block the function of the intact kinases, blocked alpha(4)beta(1) stimulation of alpha(L)beta(2)-dependent migration. These results define a proximal protein-protein interaction of an integrin cytoplasmic domain required for trans-regulation between integrins, and establish that augmented activation of Pyk2 and/or FAK is an immediate signaling event required for the trans-regulation of integrin alpha(L)beta(2) by alpha(4)beta(1).
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PMID:Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. 1279 17

Over the past 10-20 years a number of immunosuppressive drugs, such as cyclosporine A, tacrolimus, sirolimus, or mycophenolate mofetil have been approved for clinical use and have been highly successful in preventing or delaying graft rejection. Nevertheless, there is an incessant need for better and safer drugs to improve short-term and long-term outcomes following transplantation. A number of low-molecular-weight molecules that interfere with immune cell functions are in development. These include molecules that inhibit the janus protein tyrosine kinase JAK3, compounds that alter lymphocyte trafficking (the sphingosine-1-phosphate receptor antagonist FTY720), and new malononitrilamides (FK778). All seem to show promising therapeutic potential. Among the biologic agents, there are high expectations for antibodies or recombinant chimeric molecules targeting costimulatory surface molecules or pathways involved in the migration of immune cells. The list of such targets includes the ligand pairs CD28:B7, CD154:CD40, LFA-1:ICAM-1, ICOS:B7RP-1, and VLA-4:VCAM-1. However, the clinical development of drugs for transplantation has proved to be difficult, complex, and time consuming. Therefore, newly emerging drug candidates will also demand better methods for monitoring their efficacy as well as their side effects in vivo. Pharmacokinetics (PK) and pharmacodynamics (PD) are complementary approaches used to select drugs on the basis of their in vivo efficacy as well as safety. Whereas PK monitors the handling of the drug by the body, PD focuses on the biologic effect of the drug on its target. Therefore, PD studies of in vivo efficacy are useful for clinical decisions to determine the optimal dose and type of immunosuppressant. At the preclinical stage, PD is aimed at accelerating the selection of lead compounds via PD-controlled trials in animals. Moreover, PD can help to discover new mechanisms of action for a drug or a drug candidate. However, its full potential has not been used, mainly because of laborious and time-consuming methodology. This review focuses on established and novel PD/PK approaches to assess immunosuppressive compounds in the context of new evolving drugs or drug combinations.
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PMID:Pharmacodynamics in the development of new immunosuppressive drugs. 1557 Jan 81

CD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3zeta, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing protein phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
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PMID:Defective proximal TCR signaling inhibits CD8+ tumor-infiltrating lymphocyte lytic function. 1569 9


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