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)

Ligation of the CD2 cell surface glycoprotein expressed on T lymphocytes and NK cells induces protein tyrosine phosphorylation and activation of the Src kinases, LCK and FYN. We show here that in Jurkat T leukemia cells and in peripheral blood T cells, CD2 stimulation also leads to tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. Activation of EMT by CD2 was induced by mitogenic pairs of CD2 mAb, certain single CD2 mAb followed by secondary antibody cross-linking, and CD58-bearing sheep red blood cells. With the use of different Jurkat cell mutants it was demonstrated that CD2-mediated activation of EMT required expression of LCK, but not require surface expression of the CD3 zeta chain. Receptor-mediated activation of LCK does not in itself lead to activation of this Tec kinase since induction of LCK by ligation of CD4 or CD5 did not result in activation of EMT. The activation of EMT during CD2 signaling suggests an important role for this kinase in CD2 co-stimulation of T cell responses.
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PMID:CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. 894 65

A recessive mutant cell line, B7, which is partially responsive to both interferon (IFN)-alpha and IFN-gamma is described. B7 was FACS sorted from a cellular pool, which was obtained from the parental cell line 2C4, after several rounds of mutagenesis. The partial responsiveness to IFN was observed both in terms of expression of cell surface markers (CD2, class I and II HLAs) and mRNA expression of IFN-stimulated genes (9-27; 6-16; 2'-5' OAS; GBP and HLA-DR alpha). A genetic cross with the U4 mutant (JAK1-, a member of the Janus family of nonreceptor tyrosine kinase) did not restore full IFN responsiveness to B7, and JAK1 cDNA transfection into B7 restored the wild phenotype of the cell line, defining B7 as a member of the U4 complementation group. Nevertheless, JAK1 mRNA was not detected in this mutant. Transcriptional regulator complexes such as IRF1/2 (IFN-regulatory factor) and ISGF3-gamma (IFN-stimulated gene factor) were constitutively formed in the B7 mutant and co-migrated with the IFN-induced complexes expressed in the parental cell line 2C4. Thus, this cell line seems to be useful for understanding cis-acting elements governing JAK1 mRNA expression.
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PMID:A mutant cell line partially responsive to both IFN-alpha and IFN-gamma. 922 2

The beta1 integrin adhesion receptors activate signal transduction pathways that induce tyrosine phosphorylation of a variety of substrates. Increased tyrosine phosphorylation is mediated by the beta1 subunit cytoplasmic domain, which consists of 46 amino acids and contains no intrinsic kinase activity. In the H9 T cell line, beta1 integrin engagement leads to the increased tyrosine phosphorylation of three 105 to 115-kDa substrates that are distinct from focal adhesion kinase (FAK): HEF1 (human enhancer of filamentation 1), a protein with structural homology to p130Cas, and two novel substrates, pp105 and pp115. DNA-mediated gene transfer was used to explore the role of the beta1 cytoplasmic domain in integrin-mediated tyrosine phosphorylation of HEF1, pp105, and pp115 in human T cells. Using a chimeric receptor composed of the cytoplasmic domain of the beta1 integrin subunit and the extracellular and transmembrane domains of the CD2 Ag, we demonstrate that the beta1 cytoplasmic domain is necessary and sufficient for inducing tyrosine phosphorylation of each of these three substrates in H9 T cells. Analysis of a series of beta1 cytoplasmic domain truncations reveals that a truncation of only five amino acids from the carboxyl-terminal end of the beta1 cytoplasmic domain abrogates the ability of the CD2/beta1 chimera to activate tyrosine phosphorylation of HEF1, pp105, or pp115. Thus, the carboxyl-terminal five amino acids, Lys-Tyr-Glu-Gly-Lys (KYEGK), of the beta1 integrin cytoplasmic domain are critical for the coordinate tyrosine phosphorylation of three non-FAK substrates in human T cells.
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PMID:Structural requirements for beta1 integrin-mediated tyrosine phosphorylation in human T cells. 954 75

Integrin receptors play a central role in cell migration through their roles as adhesive receptors for both other cells and extracellular matrix components. In this study, we demonstrate that integrin and cadherin receptors coordinately regulate contact-mediated inhibition of cell migration. In addition to promoting proliferation (Sastry, S., M. Lakonishok, D. Thomas, J. Muschler, and A. Horwitz. 1996. J. Cell Biol. 133:169-184), ectopic expression of the alpha5 integrin in cultures of primary quail myoblasts promotes a striking contact-mediated inhibition of cell migration. Myoblasts ectopically expressing alpha5 integrin (alpha5 myoblasts) move normally when not in contact, but upon contact, they show inhibition of migration and motile activity (i.e., extension and retraction of membrane protrusions). As a consequence, these cells tend to grow in aggregates and do not migrate to close a wound. This phenotype is also seen with ectopic expression of beta1 integrin, paxillin, or activated FAK (CD2 FAK) and therefore appears to result from enhanced integrin-mediated signaling. The contact inhibition observed in the alpha5 myoblasts is mediated by N-cadherin, whose expression is upregulated more than fivefold. Perturbation studies using low calcium conditions, antibody inhibition, and ectopic expression of wild-type and mutant N-cadherins all implicate N-cadherin in the contact inhibition of migration. Ectopic expression of N-cadherin also produces cells that show inhibited migration upon contact; however, they do not show suppressed motile activity, suggesting that integrins and cadherins coordinately regulate motile activity. These observations have potential importance to normal and pathologic processes during embryonic development and tumor metastasis.
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PMID:Integrin and cadherin synergy regulates contact inhibition of migration and motile activity. 954 28

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

Specific activation of T cells requires stable cell-cell interaction; however, little is known how the transition from a previously motile state into a sessile state following activation is achieved. We investigated the direct effect of T-cell receptor (TCR)/CD3 complex engagement and/or stimulation of the accessory molecule CD2 on the locomotion of peripheral human T cells within three-dimensional (3-D) collagen lattices. Simultaneous engagement of CD3 and CD2 very potently stimulated T-cell migration, resulting in the recruitment of previously sessile cells (about 24% of the total population was additionally recruited) as well as an increase in the mean duration of active locomotion. This induction of migration was accompanied by an increased tyrosine phosphorylation of a 125 000 MW substrate corresponding to the focal adhesion kinase. Using confocal laser scanning microscopy we detected antibody-induced receptor capping into the uropod of migrating T cells whereas untreated control cells displayed an even distribution of CD3 and CD2 on the cell surface. Less pronounced induction of locomotion was achieved following triggering of CD3 or CD2 alone. Thus, in 3-D collagen lattices specific T-cell activation did not lead to cessation of cellular migration but rather induced cytoskeletal activity that ultimately resulted in vigorous locomotory activity.
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PMID:Direct and rapid induction of migration in human CD4+ T lymphocytes within three-dimensional collagen matrices mediated by signalling via CD3 and/or CD2. 976 58

The Tec protein-tyrosine kinase family includes Btk, Itk/Tsk/Emt, Tec, Rlk/Txk, and Bmx which are involved in signals mediated by various cytokines or antigen receptors. Itk is expressed primarily in T cells and activated by TCR/CD3, CD28, and CD2. However, the defect in T cell signaling in itk-deficient mice is very modest. Thus, we looked for other Tec family kinases that could be expressed in lymphoid cells and involved in T cell signal transduction. Here, we demonstrate that Tec, expressed in T cells, is activated following TCR/CD3 or CD28 ligation and interacts with CD28 receptor in an activation-dependent manner. This interaction involves the Tec SH3 domain and the proline-rich motifs in CD28. We also show that Tec can phosphorylate p62(dok), one CD28-specific substrate, whereas Itk cannot. Overexpression of Tec but not Itk can enhance the interleukin-2 promoter activity mediated by TCR/CD3 or CD28 stimulation and introduction of a kinase-dead Tec but not Itk can suppress interleukin-2 expression, indicating that Tec is directly involved in T cell activation. Altogether, these data demonstrate that Tec kinase is an integral component of T cell signaling and that the two Tec family kinases, Tec and Itk, have distinct roles in T cell activation.
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PMID:The role of Tec protein-tyrosine kinase in T cell signaling. 987 94

Mutant cell lines B3 and B10, which are unresponsive to both interferon (IFN)-alpha and IFN-gamma, and line B9, which does not respond to IFN-gamma stimulation, are described. The mutants were submitted to fluorescence-activated cell sorting (FACS) from a cellular pool, which was obtained from the parental cell line 2C4 after several rounds of mutagenesis. The unresponsiveness to IFN stimulation was observed both in terms of expression of cell surface markers (CD2, class I and II HLAs) and mRNA expression of IFN-stimulated genes (2'-5' oligoadenylate synthetase (OAS), 9-27, and guanylate binding protein (GBP)). Genetic crossing of B3, B9 and B10 with U3 (STAT1-), gamma 2a (JAK2-) and U4 (JAK1-) mutants, respectively, did not restore IFN responsiveness to the hybrid cell lines. However, when these cell lines were crossed with the same mutants, but using the pairwise crosses B3 x U4, B9 x U3 and B10 x U3, the cell hybrids recovered full IFN responsiveness. The present genetic experiments permitted us to assign the mutant cell lines B3, B9 and B10 to the U3, gamma 2 and U4 complementation groups, respectively. These conclusions were supported by the analysis of IFN-stimulated genes in the mutants.
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PMID:JAK/STAT-deficient cell lines. 992 Dec 73

The pattern of expression of the human Emt tyrosine kinase was established in healthy individuals and hematological malignancies by RT-PCR from bone marrow and blood samples, fractionated into T-cells, B-cells, monocytes, granulocytes and thrombocytes. Previously studied mostly in murine samples or established human cell lines, the in vivo correlation was here further clarified. In hematopoietic cells, expression of the EMT gene was associated with T-cell fractions, but Emt was not detected in cord blood CD34+ cells. In fetal tissues, Emt mRNA was strongly expressed in thymus, no expression could be detected in non-hematopoietic tissues. The expression pattern of the 48 malignant bone marrow samples (23 ALL, 1 PLL, 9 AML, 7 CLL and 8 CML cases) paralleled the findings from normal hematopoietic cells: 9/11 T cell associated ALLs, as well as one T-PLL sample, but only 1/12 samples of B-ALL expressed Emt markedly. Only minor signs of Emt expression could be shown in the AML samples, while CML and CLL samples were totally devoid of expression. In addition the Emt protein could be detected by Western blotting from T-lymphocytes and T-cell associated ALL, corresponding to mRNA expression. In conclusion, Emt (Itk) is T-cell associated both in normal and leukemic cells, but is not expressed in cord blood CD34+ cells, suggesting that Emt expression is switched on only later in T-cell development. In addition, an association between Emt and CD2 expression remains even in malignancies.
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PMID:Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies. 1004 24

The Emt/Itk/Tsk tyrosine kinase is involved in intracellular signaling events induced by several lymphocyte surface receptors. Modulation of TCR/CD3-induced phospholipase-C gamma 1 (PLC gamma 1) activity by the tyrosine kinase Emt/Itk/Tsk has been demonstrated based on studies of Itk-deficient murine T lymphocytes. Here we report a TCR/CD3-regulated association between Emt and PLC gamma 1 in both normal and leukemic T cells. In addition, this association was enhanced following independent ligation of the CD2, CD4, or CD28 costimulatory molecules, but not of CD5 or CD6 surface receptors, correlating to the induced tyrosine phosphorylation of Emt. Before Ab-induced T cell activation, we found that the Emt-SH3 domain was crucial for the constitutive Emt/PLC gamma 1 association; however, upon TCR/CD3 engagement, the Emt-SH2 domain was more efficient in mediating the enhanced Emt/PLC gamma 1 interaction. Furthermore, the PLC gamma 1-SH3 domain, but not the two PLC gamma 1-SH2 domains, contributed to formation of the protein complex. Thus, we describe a regulated interaction between Emt and PLC gamma 1, and based on our studies with individual Emt and PLC gamma 1 SH2/SH3 domains, we propose a mechanism for this association.
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PMID:Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes. 1058 33


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