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)

Signal transduction of cytokine receptors is mediated by the JAK family of tyrosine kinases. Recently, the kinase partners for the interleukin (IL)-2 receptor have been identified as JAK1 and JAK3. In this study, we report the identification of splice variants that may modulate JAK3 signaling. Three splice variants were isolated from different mRNA sources: breast (B), spleen (S), and activated monocytes (M). Sequence analysis revealed that the splice variants contain identical NH2-terminal regions but diverge at the COOH termini. Analyses of expression of the JAK3 splice isoforms by reverse transcriptase-polymerase chain reaction on a panel of cell lines show splice preferences in different cell lines: the S-form is more commonly seen in hematopoietic lines, whereas the B- and M-forms are detected in cells both of hematopoietic and epithelial origins. Antibodies raised against peptides to the B-form splice variant confirmed that the 125-kDa JAK3B protein product is found abundantly in hematopoietic as well as epithelial cells, including primary breast cancers. The lack of subdomain XI in the tyrosine kinase core of the B-form JAK3 protein suggests that it is a defective kinase. This is supported by the lack of detected autokinase activity of the B-form JAK3. Intriguingly, both the S and B splice isoforms of JAK3 appear to co-immunoprecipitate with the IL-2 receptor from HUT-78 cell lysates. This and the presence of multiple COOH-terminal splice variants coexpressed in the same cells suggest that the JAK3 splice isoforms are functional in JAK3 signaling and may enrich the complexity of the intracellular responses functional in IL-2 or cytokine signaling.
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PMID:A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells. 755 33

CD28 costimulatory signals are required for lymphokine production and T cell proliferation. CD28 signaling recruits the intracellular proteins PI 3-kinase, ITK, and GRB-2/SOS. PI 3-kinase and GRB-2/SOS bind the CD28 cytoplasmic pYMNM motif via SH2 domains. We generated CD28 pYMNM mutants and found that Y191 mutation (Y191CD28F) disrupted both PI 3-kinase and GRB-2 binding, while M194 mutation (M194CD28C) disrupted only PI 3-kinase binding. Both mutants still bound ITK. We have assessed the ability of these selective mutants to support IL-2 production upon TCR zeta/CD3 ligation in the presence of CHO-CD86 (B7-2) cells. Both Y191CD28F and M194CD28C mutants failed to generate IL-2. These data directly implicate PI 3-kinase in CD28-mediated costimulation leading to IL-2 secretion. Wortmannin, an inhibitor of PI 3-kinase, induced cell apoptosis and as such was unsuitable for use in this study.
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PMID:Selective CD28pYMNM mutations implicate phosphatidylinositol 3-kinase in CD86-CD28-mediated costimulation. 758 33

Members of the Janus family (JAK) of protein tyrosine kinases are critical enzymes in signaling pathways via hematopoietin receptors. We have cloned JAK3, which unlike other known family members (JAK1, JAK2, and TYK2) is preferentially expressed in hematopoietic cells but not in a variety of other cells. Functionally, JAK3 and JAK1 are coupled to the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 in T cells and NK cells. Because of the importance of IL-2, IL-4, and IL-7 in B cell physiology, we sought to determine whether JAK3 was also present in B lymphocytes and whether it was involved in signaling via cytokines that are important for B cell development and function. In this report, we demonstrate that JAK3 is expressed in normal human peripheral blood B cells at levels that are comparable to those in T cells. In addition, the levels were found to be markedly up-regulated following stimulation with staphylococcal protein A Cowan and anti-CD40 Abs. In addition, IL-4 and IL-7 induced the rapid tyrosine phosphorylation of JAK3 and JAK1, and IL-4 activated both JAK3 and JAK1 phosphotransferase activity. JAK3 protein was also detected in immature B cell lines, but not in more well differentiated cell lines. Additionally, JAK3 was detected in lysates from bone marrow lymphoblasts of patients with B cell precursor acute lymphocytic leukemia and cell lines derived from human B cell lymphomas. Together, these data suggest that the regulation of JAK3 expression and activity is likely to be important in B cell development and function.
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PMID:Regulation of JAK3 expression and activation in human B cells and B cell malignancies. 759 33

The gene regulatory functions of the human IL-2 receptor (IL-2R) were reconstituted in transiently transfected hepatoma cells. The combination of IL-2R beta and -gamma mediated a strong stimulation via the cytokine response element of the alpha 1-acid glycoprotein gene and the hematopoietin receptor response element, but none via the IL-6 response element or the sis-inducible element. IL-2R alpha enhanced 10-fold the sensitivity of the IL-2R beta.gamma complex to respond to IL-2 or IL-15, but did not modify the specificity or the magnitude of maximal gene regulation. A homodimerizing chimeric receptor G-CSFR-IL-2R beta could mimic the IL-2R action. The IL-2R-mediated gene regulation was similar to that seen with receptors for IL-4 and IL-7, but differed from that for IL-6 type cytokines, thrombopoietin, erythropoietin, and growth hormone. The activation of STAT proteins by the IL-2R was assessed in transfected L-cells and COS-1 cells. Although IL-2R subunits were highly expressed in these cells, no STAT protein activation was detectable. Transient overexpression of JAK3 was unable to change the signaling specificity of the hematopoietin receptors in rat hepatoma, L-, and COS cells, but established a prominent activation of the IL-6 response elements by the IL-2R and IL-4R in HepG2 cells. The data support the model that the IL-2R and related hematopoietin receptors produce at least two separate signals which control gene expression.
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PMID:The action of interleukin-2 receptor subunits defines a new type of signaling mechanism for hematopoietin receptors in hepatic cells and fibroblasts. 771 38

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large proportion of human and mouse lymphocytes. Agonistic antibodies to CD38 induce a strong proliferative response in lymphocytes additionally co-stimulated with other growth co-factors such as IL-4, IL-2 plus accessory cells or sub-mitogenic doses of endotoxin. We show here that B lymphocytes from unstimulated X-linked immunodeficient (xid) mice are unresponsive to CD38 stimulation, both in terms of proliferative response and surface antigen modulation. This CD38 unresponsiveness is evident in the presence of excess quantities of, and normal responses to, the accessory growth co-stimulants required for this response. CD38 molecules expressed on xid B cells are normal in terms of expression levels, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent proposal that the xid gene encodes a tyrosine kinase called Bruton's tyrosine kinase (btk), these data suggest that btk is either an integral component or an indirect regulator of the CD38-induced signal transduction pathway.
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PMID:CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction. 773 14

The proliferation of activated T lymphocytes is critically dependent on the binding of the T-cell growth factors, interleukin (IL)-2 and IL-4, to distinct but evolutionarily related cell surface receptors. Previous results suggest that the IL-2 receptor (IL-2R) and IL-4R are coupled to both overlapping and distinct intracellular signaling pathways in T lymphocytes. In this study, we demonstrate that activation of Janus tyrosine kinases (JAKs) and STAT transcription factors is rapidly induced by exposure of factor-dependent murine T-cell lines to IL-2 or IL-4. Both IL-2 and IL-4 stimulated the rapid activation of JAK1 and JAK3, whereas JAK2 activity was unaffected by either cytokine. These responses were accompanied by the appearance in cell nuclei of 3 DNA binding activities that recognized a high-affinity binding site for STAT factors. In transient transfection assays, this STAT factor target sequence conferred IL-2 and IL-4 inducibility on a synthetic luciferase reporter gene. Antibody supershifting experiments indicated that IL-2 induces the formation of STAT dimers containing STAT3 and STAT1 alpha. Although IL-4 also activated STAT1 alpha, the major IL4-induced STAT factor is not STAT3 and remains undefined. Pretreatment of the T-cells with the protein-tyrosine kinase inhibitor herbimycin A blocked both the nuclear translocation of STAT factors and STAT-dependent reporter gene transcription. Immunoblot analyses confirmed that cytoplasmic STAT3 was heavily phosphorylated on tyrosine in IL-2-stimulated cells, and that phosphorylated STAT3 appeared in the nuclei of these cells. These results indicate that identical JAKs and partially overlapping sets of STATs are activated by IL-2 and IL-4 in T lymphocytes.
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PMID:Protein-tyrosine kinase-dependent activation of STAT transcription factors in interleukin-2- or interleukin-4-stimulated T lymphocytes. 774 3

The protein-tyrosine kinase gene Itk is expressed preferentially in T lymphoid cells of the mouse and is induced by IL-2. A related gene, Btk, is expressed in the murine B lymphoid and myeloid lineages. Because mutations in Btk and the corresponding human gene are associated with X-linked immunodeficiency syndromes, it was of interest to map Itk and its human counterpart. By Southern blot analysis of DNA from the progeny of two multilocus crosses, murine Itk was mapped to Chromosome 11. By fluorescence in situ hybridization, human ITK was mapped to 5q32-q33. Murine Itk and its human homologue lie within regions of conserved synteny that include several growth factor and growth factor receptor genes. This region in humans is frequently deleted in the myelodysplastic syndrome, suggesting possible involvement of ITK in this disorder.
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PMID:Mapping of the gene for the tyrosine kinase Itk to a region of conserved synteny between mouse chromosome 11 and human chromosome 5q. 782 87

In addition to being an iron transporter, the transferrin receptor (TfR) has been shown to play a role in T cell activation. Stimulation of the TfR with specific Abs results in T cell proliferation, IL-2 secretion, and protein kinase C activation. In this paper we have analyzed early events caused by activation of the TfR. We have found several protein substrates to be tyrosine phosphorylated upon TfR stimulation in the human Jurkat T cell line. Interestingly, the TfR induced tyrosine phosphorylation in cell lines expressing TCR but not in TCR-negative mutants. Restoration of the TCR surface expression in these mutants reestablished the ability of the TfR to induce tyrosine phosphorylation. This result suggests that activation through the TfR is functionally dependent upon the expression of the TCR. Moreover, the functional relationship of the TfR with the TCR complex is also supported by data showing that TfR stimulation resulted in the tyrosine phosphorylation of the TCR zeta-chain; conversely, stimulation of the TCR complex resulted in an increased tyrosine phosphorylation of the TfR. More importantly, the TfR is shown to associate physically with the TCR zeta-chain as well as with the zeta-binding ZAP70 tyrosine kinase. The TfR/zeta complex is expressed on the cell surface independent of the expression of the other subunits of the TCR complex. We suggest that the TfR/zeta complex is responsible for transducing the TfR-induced signals, and that it could serve to amplify signals delivered by Ag binding to the TCR.
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PMID:Transferrin receptor induces tyrosine phosphorylation in T cells and is physically associated with the TCR zeta-chain. 783 51

The activation of Janus protein tyrosine kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins by interleukin (IL)-2, the T cell antigen receptor (TCR) and interferon (IFN) alpha was explored in human peripheral blood-derived T cells and the leukemic T cell line Kit225. An IL-2-induced increase in JAK1 and JAK3, but not JAK2 or Tyk2, tyrosine phosphorylation was observed. In contrast, no induction of tyrosine phosphorylation of JAKs was detected upon stimulation of the TCR. IFN alpha induced the tyrosine phosphorylation of JAK1 and Tyk2, but not JAK2 or JAK3. IFN alpha activated STAT1, STAT2 and STAT3 in T cells, but no detectable activation of these STATs was induced by IL-2. However, IL-2 regulates the DNA binding and tyrosine phosphorylation of two STAT-like protein complexes which do not include STAT1, STAT2 or STAT3. STAT4 is not activated by IL-2. The activation of STAT5 cannot be excluded, so the IL-2-activated complexes most probably include at least one novel STAT. No STAT activity was detected in TCR-stimulated lymphocytes, indicating that the JAK/STAT pathway defined in this study constitutes an IL-2R-mediated signaling event which is not shared by the TCR. Finally, in other cell types the correlation between JAK1 activation and the induction of STAT1 has suggested that JAK1 may activate STAT1. The observation that IL-2 and IFN alpha activate JAK1 to a comparable degree, but only IFN alpha activates STAT1, indicates that JAK1 activation is not the only determining factor for STAT1 activation. Moreover, the data show that JAK1 stimulation is also not sufficient for STAT3 activation.
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PMID:Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. 798 57

Activation of the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2R beta and IL-2R gamma chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2R beta antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2R beta, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2R beta through binding of the kinase domain to the acidic domain of IL-2R beta. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2R beta is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Thus members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-kappa B, and increased expression of Raf-1, Pim-1, bcl-2, IL-2R alpha and IL-2R beta, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane signaling by the interleukin-2 receptor: progress and conundrums. 826 Jun 51


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