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)

In 1987, data from the Centers for Disease Control AIDS data base indicated a 50% prevalence of oropharyngeal Candida infection, a 10% rate of esophageal infection, and .5% rate of bronchopulmonary infection among AIDS patients. Candida-positive blood cultures were found in 13 of 903 AIDS patients, and disseminated Candida infection was ascertained in 11 of 101 post mortem examinations of AIDS victims. 5 of 12 patients with oral Candida infection progressed to AIDS within a 42-week investigation as opposed to only 1 of 17 patients without Candida. In the former group, CD4 counts and CD4/CD8 ratios were also significantly lower. Most infections were caused by Candida albicans. Genital Candida occurs in 5-20% of women in reproductive age. In a study of 66 HIV-infected women Candida vaginitis preceded oral Candida infections which preceded Candida esophagitis. 33 women had vaginal infection, 25 had oral Candida, and 9 had esophageal infection with reduced CD4 counts. Infections of the oropharynx and the vagina are reduced CD4 counts. Infections of the oropharynx and the vagina are treated with amphotericin B, nystatin, miconazole, and clotrimazole. Systemically effective compounds include ketoconazole, itraconazole, and fluconazole, although interactions with rifampicin, phenobarbital, and phenytoin used in HIV treatment occur. Fluconazole is contraindicated in C. glabrata and C. krusei infections as it selects for azole-resistant Candida strains. Iv amphotericin B and fluconazole are used in serious infections when oral treatment is ineffective.
Int J STD AIDS
PMID:Candida infections in AIDS patients. 161 60

The thymic stroma plays a critical role in the generation of T lymphocytes by direct cell-to-cell contacts as well as by secreting growth factors or hormones. The thymic epithelial cells, responsible for thymic hormone secretion, include morphologically and antigenically distinct subpopulations that may exert different roles in thymocyte maturation. The recent development of thymic epithelial cell lines provided an interesting model for studying thymic epithelial influences on T cell differentiation. Treating mouse thymocytes by supernatants from one of TEC line (IT-76M1), we observed an induction of thymocyte proliferation and an increase in the percentages of CD4-/CD8- thymocytes. This proliferation was largely inhibited when thymocytes were incubated with IT-76M1 supernatants together with an anti-thymulin monoclonal antibody, but could be enhanced by pretreating growing epithelial cells by triiodothyronine. We suggest that among the target cells for thymulin within the thymus, some putative precursors of early phenotype might be included.
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PMID:Induction of thymocyte proliferation by supernatants from a mouse thymic epithelial cell line. 190 86

Clinical and experimental data suggest a role for the immune response in preventing leukemic relapses following allogeneic bone marrow transplantation the graft-versus-leukemia (GVL) effect. In the context of an allogeneic BMT, a number of different immune mechanisms mediated by donor cells may be responsible for the GVL effect. We have approached this question by using limiting dilution cultures of alloactivated human lymphocytes to analyze the in vitro allogeneic cytolytic response against fresh allogeneic leukemia. Initial results in the limiting dilution assays with split culture analyses demonstrated frequent alloreactive cytolytic T lymphocyte precursors that destroyed remission peripheral blood lymphocytes and leukemic cells from the allogeneic leukemic patient. These assays also demonstrated frequent lymphokine-activated killer (LAK) cell precursors that lysed both the LAK sensitive Daudi line and the allogeneic leukemia. In these experiments, isolated cultures also showed cytolytic activity directed against the allogeneic leukemic blasts without activity against remission PBL, or the LAK-sensitive Daudi cell line. Two T cell lines (ABL1 and ABL2) isolated from an LDA, demonstrated this form of specificity, mediating destruction specifically against the allogeneic acute lymphoblastic leukemic cells. Both cell lines ABL1 and ABL2 were CD3+, TCR alpha beta +, and CD4+. These 2 cell lines mediated little or no cytotoxicity against a large panel of other targets tested (natural killer sensitive and resistant cell lines, allogeneic PBL, and allogeneic fresh leukemic blasts). Antibody-blocking experiments revealed a role for the CD3-TCR receptor of both cell lines in lysis of leukemic cells; the CD4 and MHC class II molecules were clearly involved in the lysis by the ABL1 cell line. Specificity of recognition for the allogeneic leukemic blasts was further confirmed by unlabeled target competitive inhibition studies. The mechanism of the preferential lysis of leukemia by the alloactivated T cell lines described in this paper remains uncertain. Nevertheless, these leukemic-specific populations provide a means by which the human GVL effect may be further studied in vitro.
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PMID:Specific recognition of human leukemic cells by allogeneic T cell lines. 257 Dec 6

The cytoplasmic protein tyrosine kinase p56lck (Lck) has important signaling roles in T-cell development and activation. We have mutated the two known regulatory tyrosine residues of CD4-associated Lck and examined the effects on its kinase-dependent function in an antigen-specific CD4-dependent T-cell hybridoma. Substitution of phenylalanine for the negative regulatory tyrosine-505 within a CD4/Lck chimera resulted in a slightly increased response to antigen, whereas mutation of the major in vitro autophosphorylation site (tyrosine-394) completely abolished the kinase-dependent function of Lck. Even though its kinase activity was only slightly affected, the F394 mutant behaved similarly to a catalytically inactive chimeric protein. Cross-linking of the F505 mutant, but not of wild-type Lck or F394 mutants, resulted in tyrosine phosphorylation of multiple cellular proteins. Although the pattern of tyrosine phosphorylation resembled that observed upon T-cell receptor cross-linking, there was no induction of interleukin-2 synthesis upon cross-linking of the chimeric protein. These results suggest that the activity of the Lck kinase domain in vivo is controlled by dephosphorylation at the negative regulatory site and phosphorylation at the positive regulatory (autophosphorylation) site. Additionally, our data show that the specific kinase activity of Lck towards an artificial substrate need not correlate with its ability to phosphorylate cellular proteins or its biological function.
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PMID:The kinase-dependent function of Lck in T-cell activation requires an intact site for tyrosine autophosphorylation. 748 6

One of the earliest responses of T and B lymphocytes to stimulation through their antigen receptors is the activation of protein tyrosine kinases and the tyrosine phosphorylation of multiple cellular substrates. Here we describe a tyrosine kinase substrate, fakB, a putative homologue of the focal adhesion kinase pp125FAK. Tyrosine phosphorylation of fakB was rapidly augmented in human T and B cells following antigen receptor cross-linking with antibody, while pp125FAK was nonresponsive. Costimulation of the T-cell antigen receptor (TCR/CD3) with either the CD2 or CD4 costimulatory receptors induced synergistic fakB tyrosine phosphorylation in normal human T cells. Engagement of TCR/CD3 induced the stable association of fakB with ZAP-70, the TCR/CD3 sigma-chain-associated tyrosine kinase involved in antigen receptor-induced T-cell activation. In addition, preformed complexes of fakB and ZAP-70 were observed in T-cell leukemia lines. Phosphorylation of fakB on serine, threonine, and tyrosine residues was observed both in vivo and in vitro, where a functional increase of in vitro kinase activity was observed following TCR/CD3 stimulation. fakB is thus a focal adhesion kinase-related tyrosine kinase substrate that is differentially regulated from that of pp125FAK and likely plays a role in antigen-induced lymphocyte signaling.
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PMID:Lymphocyte antigen receptor activation of a focal adhesion kinase-related tyrosine kinase substrate. 752 94

T-cell activation requires cooperative signals generated by the T-cell antigen receptor zeta-chain complex (TCR zeta-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, zeta-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.
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PMID:p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation. 756 38

Monoclonal mouse IgG3 antibody (ABL 364) against the carbohydrate Le(y) antigen enhanced infection in vitro with HTLV-1 and with HIV-1 when propagated in both transformed and normal lymphocytes. Enhancement was independent of complement, occurred with both lymphocytes and monocytes as target cells, and did not use either L(ey) epitopes on target cells for cross-linkage of virus to the cell or the Fc part of the antibody as a ligand for any cellular receptor. For enhancement to occur, binding of anti-Le(y) antibody to virus was required to take place before virus binding to its specific receptor with no indication of any alternative pathway of infection, as evidenced by abrogation of enhancement by anti-CD4 MAb or soluble recombinant CD4, and also the inability of anti-Le(y) MAb to mediate HIV infection of HSB-2 cells in which HTLV-1/HIV pseudovirus infection was enhanced. While F(ab)2 fragments of ABL 364 also enhanced infection, a human/mouse chimeric antibody and a fully humanized antibody had no enhancing effect on free virus infection. We suggest that binding of anti-Le(y) ABL 364 or its F(ab)2 fragment induced a conformational change in the gp120 oligomers facilitating the process of infection, and that this function was abrogated by the IgG1 Fc of the chimeric and the humanized antibodies. The observations indicate that the non-paratope domains of antiviral antibodies can influence their function as neutralizing or enhancing for infection.
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PMID:Enhancement of retroviral infection in vitro by anti-Le(y) IgG: reversal by humanization of monoclonal mouse antibody. 790 6

The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.
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PMID:A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. 791 25

Splenectomy has been reported to alter inconsistently the CD4 lymphocyte numbers in patients infected with the human immunodeficiency virus (HIV). To further assess the effect of splenectomy we have retrospectively examined the charts of 10 patients who were infected with HIV and who had undergone splenectomy. There was a significant increase in the mean CD4 numbers following splenectomy (mean increase of 326/microliters, or 2.1-fold, P = 0.0009), the total lymphocyte numbers (mean increase of 1.55/ml, or 2.2-fold, P = 0.001) and in the CD8 lymphocyte count (mean increase of 968/microliters, or 2.3-fold, P = 0.014). No significant difference was observed in the percentage CD4 lymphocytes (P = 0.95) or in the CD4:CD8 lymphocyte ratio (P = 0.76). In two patients, symptoms suggestive of impaired immune function developed post-splenectomy, at a time when their CD4 lymphocyte numbers were markedly higher than their pre-splenectomy values. One developed oral candidiasis (CD4 960/microliters, percentage CD4 32%), and in one patient a 7 kg weight loss was associated with recurrent mouth ulcers (CD4 680/microliters, percentage CD4 7%). We conclude that the total CD4 count increases significantly after splenectomy while the percentage CD4 lymphocyte count and CD4:CD8 lymphocyte ratio do not. Our data suggest that the CD4 lymphocyte count overestimates the immune function in these patients, although our findings are not conclusive.
Int J STD AIDS
PMID:CD4 lymphocyte numbers after splenectomy in patients infected with the human immunodeficiency virus. 791 47

Two-dimensional gel electrophoresis of in vitro phosphorylated proteins coprecipitated by CD2 monoclonal antibody (mAb) from Brij58 lysates of resting human T lymphocytes and natural killer (NK) cells resulted in the identification of a novel 29/30-kD disulfide-linked dimer (pp29/30). Comparative two-dimensional analysis of CD2, CD3, CD4, CD5, and CD8 immunoprecipitates revealed that pp29/30 associates with these signaling receptor complexes but not with CD18, CD27, and CD29 in human T lymphocytes. Analysis of CD2 immunoprecipitates prepared from T cell antigen receptor/CD3-modulated T lymphocytes indicated that pp29/30 preferentially associates and comodulates with the human T cell antigen receptor (TCR). Since tyrosine phosphorylated pp29/30 selectively interacts with the Src homology type 2 domains (SHZ) of the protein tyrosine kinases p56lck and p59fyn but not ZAP70 the present data suggest that pp29/30 represents a novel signaling receptor associated phosphoprotein likely involved in the activation of human T lymphocytes and NK cells.
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PMID:Identification of a novel dimeric phosphoprotein (PP29/30) associated with signaling receptors in human T lymphocytes and natural killer cells. 791 8


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