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)

Recently, the SRC-like non-receptor protein tyrosine kinase p56-LCK has been shown to physically associate with the interleukin-2 receptor (IL-2-R) complex and to undergo rapid elevations in its tyrosine kinase activity upon stimulation of T lymphocytes with IL-2. The functional significance of p56-LCK kinase activation for IL-2-mediated lymphocyte responses, however, has never been directly assessed. Using gene transfer approaches, we have achieved markedly elevated levels of p56-LCK kinase activity in the IL-2-dependent cytolytic T-cell line CTLL-2 and the helper line HT-2. CTLL-2 and HT-2 cells that were stably transfected with expression plasmids encoding either the normal human p56-LCK or a constitutively active version of the mouse p56-LCK kinase (LCK[Y505]) contained striking elevations in the levels of tyrosine phosphorylation on several proteins (34-36, 50-60, 62-68, 77-78, 104-110 kDa), as determined by immunoblot analysis using anti-phosphotyrosine antibodies. CTLL-2 and HT-2 LCK- and LCK(Y505F)-transfected cells remained dependent on IL-2 for their growth and survival in culture despite the findings that (i) IL-2 specifically stimulated elevations in the activity of the endogenous p56-LCK in untransfected CTLL-2 cells without affecting the activities of the other SRC-like kinases in these cells (p59-FYN, p62-YES) and that (ii) IL-2-mediated regulation of p56-LCK correlated with IL-2-driven proliferation of these T cells. Specifically, no elevation in the proliferation (DNA synthesis) or growth of these T cells was found at any of the concentrations of IL-2 examined (0.01-25 U/ml), relative to untransfected and control transfected cells. Furthermore, when cultured in the absence of IL-2, transfected T cells whose relative levels of p56-LCK activity were elevated by approximately 20-50-fold died with the same kinetics as control cells and underwent apoptosis, as defined by uptake of trypan blue dye and DNA fragmentation assays, respectively. Taken together, these data indicate that while IL-2 can up-regulate the enzymatic activity of p56-LCK, elevated levels of p56-LCK tyrosine kinase activity are insufficient to stimulate IL-2-mediated pathways required for T-cell growth and survival. These findings thus imply the existence of other signal-transducing molecules, besides p56-LCK, that physically participate in IL-2R complexes and that are necessary for initiation of the biochemical events ultimately responsible for IL-2's pleiotropic actions on lymphocytes.
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PMID:Gene transfer investigations of p56-LCK function in IL-2-dependent T-cell lines: implications for mechanisms of IL-2-signal transduction. 129 28

Epidermal growth factor (EGF) or platelet-derived growth factor binding to their receptor on fibroblasts induces tyrosine phosphorylation of PLC gamma 1 and stable association of PLC gamma 1 with the receptor protein tyrosine kinase. Similarly in lymphocytes, cross-linking of antigen receptors induces the formation of molecular complexes incorporating PLC gamma 1; however, associated kinase activity is thought to be mediated through cytoplasmic protein tyrosine kinase(s). In this report, we generated a fusion protein containing the SH2 domains of human PLC gamma 1 and human IgG1 heavy chain constant region to identify lymphocyte phosphoprotein-binding PLC gamma 1 SH2 domains following cellular activation. As in EGF- or platelet-derived growth factor-stimulated fibroblasts, PLC gamma 1 is coprecipitated in activated lymphocytes, complexed with associated tyrosine-phosphorylated proteins. One of these, a 35/36-kDa protein found prominently in T cells and at lower levels in B cells, bound to the fusion protein in immunoprecipitation experiments. The fusion protein showed lineage restricted association with a 74-kDa phosphoprotein in T cells and a 93-kDa phosphoprotein in B cells. It bound to activated EGF receptor in fibroblasts as expected, and protein tyrosine kinase activity was precipitated from EGF-stimulated cells. However, PLC gamma 1-associated protein tyrosine kinase activity was not detected in activated lymphocytes. These data suggest that lymphocyte PLC gamma 1 SH2-binding proteins are cell lineage specific and may be transiently associated with activated PLC gamma 1.
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PMID:Lymphocyte lineage-restricted tyrosine-phosphorylated proteins that bind PLC gamma 1 SH2 domains. 132 23

FAK is a unique non-receptor protein tyrosine kinase that was found in cellular focal adhesions. An increasing number of in vitro observations has suggested that FAK mediates signaling through integrins brought about by interactions with extracellular matrix (ECM). It is highly tyrosine-phosphorylated in v-src-transformed cells and during embryogenesis. To clarify the function of FAK in cell-ECM interactions, embryonic phenotype of its mutant was analysed. FAK-deficient embryos could implant and initiate gastrulation normally, but showed abnormalities in subsequent development. The abnormalities were characterized as a general deficiency in mesoderm, and the phenotype was quite similar to that caused by fibronectin-deficiency. The results suggest that FAK mediates fibronectin-integrin interactions uniquely at this stage of development, thereby playing an essential role in development of mesodermal cell lineages.
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PMID:Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. 747 17

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

FES is a non-receptor protein tyrosine kinase expressed in hematopoietic progenitors and differentiated myeloid cells. It has recently been implicated in granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and erythropoietin signal transduction. To better understand the role played by FES in normal and neoplastic hematopoiesis, we used cell fractionation techniques to examine the subcellular localization of FES in myeloid cells and cell lines. FES was observed in the nuclear, granular and plasma membrane fractions of primary human neutrophils and the myeloid leukemia cell line, HL-60. The nuclear localization was confirmed by immunocytochemistry of neutrophils.
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PMID:Human c-FES is a nuclear tyrosine kinase. 770 Jun 50

The focal adhesion kinase, pp125FAK, is a novel non-receptor protein tyrosine kinase expressed in different cells including mast cells. Here we report that a 77-kDa protein associates with pp125FAK in the mast cell analog, rat basophilic leukemia (RBL-2H3) cells. When pp125FAK immunoprecipitates were subjected to an in vitro kinase assay, there was prominent phosphorylation on tyrosine of pp125FAK and of a 77-kDa protein. By V8 protease digestion mapping and by immunoblotting with two different anti-pp125FAK antibodies, the 77-kDa protein was distinct from pp125FAK. This Fak Associated Protein or FAP was detected in RBL-2H3 cells but not in fibroblasts. The aggregation of the high affinity IgE receptor, Fc epsilon RI, induced the in vivo tyrosine phosphorylation of FAP. However, there was a marked decrease in the in vitro phosphorylation of FAP in the immunoprecipitates from Fc epsilon RI aggregated cells. Both of these Fc epsilon RI-mediated effects were enhanced by cell adhesion. There was strong association of FAP with non-tyrosine-phosphorylated pp125FAK. Thus this interaction does not appear to be mediated by the Src homology 2 domain. Together the data indicate that FAP associates with pp125FAK and suggest that FAP may play a role in Fc epsilon RI signaling.
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PMID:A 77-kDa protein associates with pp125FAK in mast cells and becomes tyrosine-phosphorylated by high affinity IgE receptor aggregation. 774 83

The proto-oncogene c-eyk, the cellular counterpart of a transforming oncogene, v-eyk, encodes a receptor protein tyrosine kinase with a distinctive extracellular region. We now demonstrate that c-Eyk can be constitutively activated through dimerization, and that the active Eyk displays a unique signaling pattern. When the kinase domain of c-Eyk was fused to the extracellular and transmembrane domains of CD8, the resulting chimera showed elevated kinase activity and caused cellular transformation. We found that the activated Eyk kinases, both v- and c-Eyk, constitutively stimulate the JAK-STAT pathway, while exerting little effect on other signaling routes such as the Ras-MAP kinase and the JNK pathways. The activated Eyk kinases specifically stimulate tyrosine phosphorylation of STAT1, STAT3 and JAK1. These downstream molecules also co-immunoprecipitate with the constitutively dimerized form of Eyk. The Eyk kinase activity is required for STAT1 stimulation. We found that the activation of STAT1 but not STAT3 correlates well with cellular transformation. In constitutively stimulating the JAK-STAT pathway, particularly STAT1, Eyk is unique in its downstream signaling and may be dependent on this pathway for cellular transformation.
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PMID:Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase. 888 43

BRK is a recently described non receptor protein tyrosine kinase whose mRNA was found to be expressed in human breast tumours and breast cancer cell lines. Expression of BRK in fibroblasts and mammary epithelial cells has been shown to enhance their ability to grow anchorage independently, and mammary epithelial cells expressing BRK acquire a potentiated mitogenic response to epidermal growth factor. In order to investigate further the expression of BRK in breast cancers, we have isolated monoclonal antibodies specifically recognising the protein. Whereas BRK expression was low or undetectable in normal mammary tissue and benign lesions, approximately two-thirds of breast tumours expressed appreciable levels, and 27% of tumours over expressed BRK by fivefold or more (up to 43x). This expression pattern was mirrored in a comparison of cell lines derived either from normal mammary epithelial cells or from carcinomas. BRK expression was found to be constant throughout the cell cycle, and did not vary with cell proliferation rate. A consideration of this expression data, in conjunction with BRK's demonstrated ability to deregulate the proliferation of mammary epithelial cells, supports the hypothesis that the over expression of BRK in a high proportion of breast carcinomas is a functionally important factor in their evolution.
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PMID:BRK tyrosine kinase expression in a high proportion of human breast carcinomas. 926 66

LCK is a non-receptor protein tyrosine kinase required for signal transduction via the T-cell antigen receptor (TCR). LCK N-terminus is S-acylated on Cys3 and Cys5, in addition to its myristoylation on Gly2. Here the role of S-acylation in LCK function was examined. Transient transfection of COS-18 cells, which express a CD8-zeta chimera on their surface, revealed that LCK mutants that were singly S-acylated were able to target to the plasma membrane and to phosphorylate CD8-zeta. A non-S-acylated LCK mutant did not target to the plasma membrane and failed to phosphorylate CD8-zeta, although it was catalytically active. Fusion of non-S-acylated LCK to a transmembrane protein, CD16:7, allowed its plasma membrane targeting and also phosphorylation of CD8-zeta when expressed in COS-18 cells. Thus S-acylation targets LCK to the plasma membrane where it can interact with the TCR. When expressed in LCK-negative JCam-1.6 T cells, delocalized, non-S-acylated LCK was completely non-functional. Singly S-acylated LCK mutants, which were expressed in part at the plasma membrane, efficiently reconstituted the induced association of phospho-zeta with ZAP-70 and intracellular Ca2+ fluxes triggered by the TCR. Induction of the late signalling proteins, CD69 and NFAT, was also reconstituted, although at reduced levels. The transmembrane LCK chimera also supported the induction of tyrosine phosphorylation and Ca2+ flux by the TCR in JCam-1.6 cells. However, induction of ERK MAP kinase was reduced and the chimera was incapable of reconstituting induced CD69 or NFAT expression. These data indicate that LCK must be attached to the plasma membrane via dual acylation of its N-terminus to function properly in TCR signalling.
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PMID:S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. 930 40

The brk gene encodes a non-receptor protein tyrosine kinase that consists of single SH3, SH2 and catalytic domains. Although BRK shows strongest sequence similarity to members of the SRC family of PTKs, there are several key structural and regulatory differences that place it on its own amongst non-receptor PTKs. In this study we have isolated genomic DNA clones corresponding to the human brk locus and used these to determine the intron-exon structure of the brk gene. The genomic structure of brk consists of 8 exons, whose boundaries are distinct from other non-receptor PTK family members, again indicating a structural and functional divergence. Alternate splicing of the primary brk transcript generates a distinct mRNA which encodes a truncated protein consisting of an SH3 domain and a novel C-terminal proline rich sequence. Using an antiserum raised to the SH3 domain, we have demonstrated that the product of this alternate brk transcript is expressed in the human breast tumour cell line T-47D. We have previously reported that expression of a tumour derived brk cDNA in mouse embryonic fibroblasts and human mammary epithelial cells supports anchorage independent growth, and in the latter potentiates the mitogenic response to epidermal growth factor. The protein encoded by the genomic sequence derived from normal human tissue is identical to that encoded by the tumour derived cDNA, and therefore the altered growth regulation is not associated with mutations within brk. In addition, we have identified a 5' genomic region that has promoter activity. The brk gene has been assigned to chromosome 20q 13.3 [corrected] using fluorescence in situ hybridisation (FISH).
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PMID:Characterisation and chromosome mapping of the human non receptor tyrosine kinase gene, brk. 933 26


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