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)

A case of T lymphoblastic leukemia (T-ALL) showing t(1;7)(p34;q34) as the sole karyotypic abnormality was investigated at the molecular level. Screening of a phage library of tumor DNA with a probe for the beta T cell receptor gene (TCRB), which maps to chromosomal band 7q34, resulted in the isolation of a clone containing DNA spanning the translocation breakpoint of the der(1) chromosome. This clone contained chromosome 1 DNA juxtaposed upstream of a D beta-J beta joint. Cloning of the corresponding germline region of chromosome 1 resulted in the isolation of a phage containing the breakpoint from the reciprocal, der(7), product, which showed chromosome 1 DNA joined downstream to a V beta segment. Comparison of germline and translocation clones demonstrated that breakage of chromosome 1 had occurred at the border of a tandem repeat of Alu sequences. To search for transcripts from DNA near the breakpoint, a chromosomal walk was initiated along chromosome 1. A probe consisting of chromosome 1 DNA from 24-30 kb upstream of the breakpoint hybridized to a transcript derived from the gene encoding the lymphocyte-specific tyrosine kinase p56lck, previously mapped to chromosomal band 1p34. The nonrandom nature of the breakpoints in this case was confirmed by the analysis of a second independent case of T-ALL containing a t(1;7) translocation, which was also found to show breakage within the LCK locus. The chromosomal breakpoint in the first case was localized 2 kb upstream of the lck upstream promoter and first nontranslated exon, while the breakpoint of the second case lay between the two alternative lck promoters, upstream of the second exon. Relative to normal thymus and activated T cells, levels of lck mRNA were greatly elevated in the first case and moderately elevated in the second. The existence of these translocations raises the possibility that alterations in the promoter region of the LCK locus may play a role in human cancer.
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PMID:Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia. 168 Sep 58

Polymerase chain reaction (PCR) is a novel tool for the in vitro amplification of DNA segments up to several kb. Repeated cycles of DNA synthesis by heat-stable Taq DNA polymerase enables to obtain more than 10(5) copies of the target sequence. Recently its enormous attitude of amplification has been applied for the detection of tumor-specific gene alterations. Examples include the detection of point mutation of RAS oncogenes at codons 12, 13, and 61 and the detection of minimal residual neoplastic cells in patients in complete clinical remission. Among many kinds of tumor specific gene translocations, BCR-ABL gene in t(9;22)(q34;q11) and BCL-2-IgH gene in t(14:18)(q32;q21) have been successfully PCR-amplified around their fused regions. In lymphoid malignancies gene rearrangements of T cell receptor chain or immunoglobulin heavy chain can be used as clonal markers for leukemic cells. PCR technique permits the detection of leukemia DNA at dilution of 10(-4) to 10(-6). Although further investigation of patients' follow-up in large scale is needed, this technique seems to hold promise for the monitoring of residual neoplastic cells.
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PMID:[Polymerase chain reaction (PCR)--a novel tool for the molecular diagnosis of neoplasms]. 220 61

Two patients with acute nonlymphocytic leukemia (ANLL) who had normal karyotypes at diagnosis and developed the Philadelphia (Ph) translocation during leukemia relapse are described in this report. Patient 1 relapsed with Ph-positive acute leukemia, FAB classification M1. The Ig heavy chain locus and T cell receptor gamma and beta genes of relapse cells from this patient were all found to be germline configuration confirming the diagnosis of M1 acute leukemia. Patient 2 displayed a complex karyotypic evolution leading to Ph-positive M4 relapse. Ph-positive relapse specimens from both patients expressed P185BCR-ABL protein and RNA gene products that were identified serologically and by polymerase chain amplification of the BCR-ABL RNA junction. In vitro derived myeloid cell lines from relapse M1 leukemia cells of patient 1 also expressed the P185BCR-ABL protein. In two described patients, late appearance of the Ph translocation that encodes P185BCR-ABL coincided with relapse of acute leukemia. We conclude that P185BCR-ABL may be a strong indicator of Ph-positive acute leukemias.
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PMID:P185BCR-ABL in two patients with late appearing Philadelphia chromosome-positive acute nonlymphocytic leukemia. 268 76

The beta 1 subfamily of integrins is thought to play an important role in both the adhesion/migration and proliferation/differentiation of T cells. beta 1 integrins can provide T cell costimulation through interaction of very late antigen (VLA) 4 (VLA-4) (alpha 4 beta 1) and VLA-5 (alpha 5 beta 1) with the extracellular matrix protein fibronectin (FN), or by VLA-4 binding to its cell surface ligand, vascular cell adhesion molecule (VCAM) 1. The mechanism by which beta 1 integrin members transduce T cell-costimulatory signals is poorly understood. Studies in non-T cells have demonstrated regulation of the tyrosine focal adhesion kinase pp125FAK by beta 1 integrin engagement and, most recently, indicate a role for pp125FAK in linking integrin-mediated signal transduction to the Ras pathway (Schaller, M. D., and J. T. Parsons, 1994, Curr. Opin. Cell. Biol. 6: 705-710; Schlaepfer, D. D., S. K. Hanks, T. Hunter, and P. Van der Geer. 1994. Nature (Lond.), 372:786-790). Although pp125FAK kinase occurs in T cells, there are no reports on its regulation in this cell type. The studies described in this article characterize novel regulation of pp125FAK by the T cell receptor (TCR)-CD3 antigen complex and beta 1 integrins, and provide the first account, in any cell type, of integrin alpha 4 beta 1-mediated pp125FAK tyrosine phosphorylation. We demonstrate a rapid and sustained synergistic increase in tyrosine phosphorylation of human pp125FAK in Jurkat T cells after simultaneous (a) triggering of the TCR-CD3 complex, and (b) alpha 4 beta 1 and alpha 5 beta 1 integrin-mediated binding of these cells to immobilized FN or alpha 4 beta 1 integrin-mediated binding to immobilized VCAM-1. Studies with normal peripheral blood-derived CD4+ human T blasts confirm the synergistic action of a TCR-CD3 complex-mediated costimulus with a FN- or VCAM-1-dependent signal in the induction of T cell pp125FAK tyrosine phosphorylation. In vitro kinase assays performed on pp125FAK immunoprecipitates isolated from Jurkat cells and normal CD4+ T cells identified a coprecipitating 57-kD tyrosine-phosphorylated protein (pp57), distinct from pp59fyn or pp56lck. These results indicate, for the first time, the involvement of a specific kinase, pp125FAK, in alpha 4 beta 1- and alpha 5 beta 1-mediated T cell-costimulatory signaling pathways. In addition, the data demonstrate novel regulation of pp125FAK tyrosine phosphorylation by the TCR-CD3 complex.
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PMID:T cell receptor- and beta 1 integrin-mediated signals synergize to induce tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells. 750 53

To identify genes involved in signal transduction pathways that regulate T cell activation and development, murine fetal thymocytes were screened for expression of protein tyrosine kinase family members by the polymerase chain reaction. Using this approach, a non-receptor protein tyrosine kinase, txk, was identified and cloned. Tsk is expressed in thymocytes as early as fetal day 13.5 and its expression at the mRNA level continues throughout development. Txk transcripts are present in thymocytes, peripheral T cells and mast cell lines, but are not detectable in B cell macrophage/monocyte cell lines or in non-hematopoietic fetal or adult tissues. In both thymocytes and T cells, txk transcripts are down-regulated after activation with PMA and ionomycin, concanavalin A or T cell receptor cross-linking. Sequence analysis indicates that txk contains SH2, SH3 and kinase catalytic domains and belongs to the tec family of cytoplasmic protein tyrosine kinases which includes tec, itk and btk. Its unique N-terminus contains a proline-rich region, but unlike the other tec family members, does not contain a pleckstrin homology domain. The restricted expression pattern of txk and its regulation by T cell activation make it an excellent candidate for involvement in signal transduction during thymocyte development.
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PMID:Murine txk: a protein tyrosine kinase gene regulated by T cell activation. 754 61

X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinase, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 120-kD protein present in human B cells as being bound by the SH3 domain of Btk and which, after B cell receptor stimulation, is one of the major substrates of tyrosine phosphorylation. We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120cbl provides evidence for an analogous role for p120cbl in B cell signaling pathways. The p120cbl protein is the first identified ligand of the Btk SH3 domain.
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PMID:The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase. 762 18

Stimulation of the T cell antigen receptor leads to several possible outcomes. This is especially true in thymocytes, where ligand occupancy of the receptor may promote survival or provoke cell death. Insight into the circuitry of T cell receptor signalling has been achieved in transgenic mouse model systems. In particular, two SRC-family protein tyrosine kinases, p59fyn and p56lck, have been shown to participate in controlling mature thymocyte proliferation and immature thymocyte development, respectively. Analysis of the function of p56lck has been especially instructive and has yielded data consistent with a model in which this kinase serves as the gatekeeper at a developmental checkpoint wherein T cell receptor beta chain synthesis promotes maturation and cell division. In addition, a remarkably coherent data set supports the view that p56lck regulates allelic exclusion at the T cell receptor beta locus. Further testing of putative signalling molecules in transgenic mice promises to permit elucidation of the biochemical distinctions between positively and negatively selecting stimulation pathways active during T cell development.
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PMID:Control of T cell development by non-receptor protein tyrosine kinases. 772 61

The human receptor Fc gamma RIIA for the Fc portion of IgG (Fc gamma) was expressed in a human T-cell line and conferred on these cells the ability to perform IgG antibody-stimulated phagocytosis. Crosslinking Fc gamma RIIA with anti-Fc gamma RII monoclonal antibody also induced tyrosine phosphorylation of multiple proteins including Fc gamma RIIA, ZAP-70, p72SYK, and phospholipase C gamma 1 subunit and an increase in intracellular Ca2+ concentration. The T cell receptor-associated zeta-chain was not tyrosine-phosphorylated after crosslinking of Fc gamma RIIA, suggesting that the Fc gamma RIIA-mediated signals were independent of CD3. Fc gamma RIIA-mediated signal transduction was defective in a transfected mutant T-cell line exhibiting reduced expression of the tyrosine kinases LCK and FYN. These studies indicate that certain T cells can assume phagocytic properties after transfection of cDNA encoding an Fc gamma receptor with the capability of inducing a phagocytic signal.
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PMID:Transfection of an Fc gamma receptor cDNA induces T cells to become phagocytic. 793 68

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

Activation of CD28 on T lymphocytes initiates a cascade of intracellular events, which in concert with activation of the T cell receptor, culminates in production of cytokines and a functional immune response. One of the earliest biochemical changes observed following stimulation of CD28 is tyrosine phosphorylation. We have demonstrated that both the LCK and the EMT/ITK/TSK (EMT) intracellular tyrosine kinases are activated following cross-linking of CD28. Utilizing somatic cell mutants lacking LCK, we demonstrate that functional LCK is required for CD28-induced activation of EMT as evidenced by increased tyrosine phosphorylation and kinase activity. In support of a role for LCK in EMT activation, reconstitution of a LCK-negative Jurkat T cell line by transfection with normal LCK recreates CD28-mediated EMT activation. Furthermore, co-transfection of LCK and EMT into COS-7 cells showed that EMT becomes phosphorylated in the presence of LCK. In addition, increases in EMT association with CD28 were eliminated in a LCK-negative Jurkat cell line, but were restored following transfection of wild type LCK. The data are most compatible with a model in which LCK, either directly or indirectly, initiates EMT activation and association with CD28 following ligation of CD28.
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PMID:Functional LCK Is required for optimal CD28-mediated activation of the TEC family tyrosine kinase EMT/ITK. 863 41


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