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)

5-HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells, inducing ligand-dependent focus formation. In order to assess their mitogenic and oncogenic potential in a different cell system, we transfected these receptors into CCL39 hamster fibroblasts, a well-characterized growth factor-dependent cell line. Cell clones expressing functional receptors were isolated and tested for (a) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum, (b) the response to serotonin alone or in combination with other growth factors, and (c) the capacity for anchorage-independent proliferation. In the absence or presence of serotonin, the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar. None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments, but synergy was observed between serotonin and the tyrosine kinase activating growth factors EGF and FGF. However, the major part of this effect could be abolished by an antagonist of 5-HT1b receptors, which are endogenous in CCL39 cells. The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha-ras-transfected cells. The fact that 5-HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like RAS, SRC, or FMS.
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PMID:Effects of 5-HT1C-receptor expression on cell proliferation control in hamster fibroblasts: serotonin fails to induce a transformed phenotype. 131 91

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

Proto-oncogenes, which represent the cellular progenitors of the transforming genes harbored by acute transforming oncogenic retroviruses, have been highly conserved during vertebrate evolution. In this report, we have assigned experimentally a subset of proto-oncogenes (SRC, ABL, FES, and FMS-all related to the SRC family) to Chinese hamster chromosomes by Southern filter hybridization analyses of DNAs isolated from both somatic cell hybrids and flow-sorted hamster chromosomes. These results demonstrate that several autosomal linkage groups containing proto-oncogenes originated prior to the radiation and speciation of mammals and have remained remarkably stable for nearly 80 million years.
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PMID:Oncogenes and linkage groups: conservation during mammalian chromosome evolution. 400 99

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.
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PMID:Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. 752 88

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

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA, REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2), interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR, PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions by slot-blot autoradiography and image analysis. The effects of a differentiating agent (cholera toxin) and of a tumour promoter (12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF, MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart from this variation, there were multiple differences in gene expression among normal and pathological cells (concerning all but P53, TGFB and interleukin transcripts) and between sub-types defined by the presence of alpha-sm-actin (myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB, PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress irreversibly along with the epithelium during tumoral development, and that breast cancer is not only a multi-gene but also a multi-tissue phenotype.
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PMID:Quantitative variation of proto-oncogene and cytokine gene expression in isolated breast fibroblasts. 776 44

The receptors for human interleukin-3 (IL-3) and human granulocyte-macrophage colony-stimulating factor (GM-CSF), hIL-3R, hGM-CSFR, respectively, consists of two subunits, alpha and beta, both of which are members of the cytokine receptor superfamily. Phosphorylation of tyrosine residues in the hGMR beta subunit and several cellular proteins is observed after hGM-CSF stimulation. We analyzed the role of tyrosine residues in the hGMR beta subunit and the nature of tyrosine kinase, JAK2, in hGMR signal transduction using several hGMR beta subunit mutants. In addition to the box1 region, a membrane distal region (a.a. 544-589) of the hGMR beta was required for c-fos activation. Only one tyrosine residue (Tyr577) existed within the region 544 to 589, and substitution of Tyr577 to phenylalanine in GMR beta 589 resulted in loss of c-fos activation. In contrast, the same substitution in a wild type receptor did not affect GM-CSF induced activities such as c-fos messenger RNA (mRNA) induction and proliferation, but the substitution abolished Shc phosphorylation. These results suggest that the activation of Shc is not essential for c-fos activation and several tyrosine residues cooperate for c-fos activation. It is well documented that IL-3 or GM-CSF activate JAK2 in BA/F3 cells. The role of JAK2 in IL-3/GM-CSF functions, however, is largely unknown. We examined the role of JAK2 in GM-CSF induced signaling pathways. Dominant negative JAK2 (delta JAK2) lacking the C-terminus kinase domain suppressed IL-3/GM-CSF induced c-fos activation and c-myc activation and proliferation, suggesting that JAK2 was involved in both signaling pathways. Protein tyrosine phosphatase SHP-2 (also called PTP 1D) and Shc were phosphorylated by IL-3/GM-CSF in BA/F3 cells; however, these phosphorylation events were inhibited by the expression of delta JAK2. Taken together, these results indicate the JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.
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PMID:Roles of JAK kinases in human GM-CSF receptor signal transduction. 897 26

Besides the regulation of hematopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF)induces the expression of a functional program in endothelial cells (ECs) related to angiogenesis and to their survival in the bone marrow microenvironment. ECs express specific GM-CSF high-affinity binding sites, which mediate the proliferative and migratory response. We now report that ECs express the alpha and beta subunits of GM-CSF receptor (GM-CSFR), and that GM-CSF is able to activate the Janus kinase (JAK)2, a member of the cytosolic tyrosine kinase family, which is known to mediate signals of several non-tyrosine kinase receptors. JAK2 tyrosine phosphorylation, as well as activation of its catalytic activity, is induced by subnanomolar concentrations of GM-CSF and occurs within 3 minutes of stimulation and persists at least for 10 minutes. The effect is specific as inferred by the lack of effect of heat-inactivated GM-CSF or neutralized by specific antibodies and by the finding that interleukin-5, which utilizes a specific alpha chain and the same beta chain of GM-CSFR, does not phosphorylate JAK2. Furthermore, we show that the amount of JAK2 physically associated with GM-CSFR beta chain is increased after GM-CSF stimulation and that GM-CSF triggers both beta chain and JAK2 tyrosine phosphorylation. Taken together, these results suggest that biologic activities of GM-CSF in vascular endothelium may, in part, be elicited by GM-CSFR-mediated JAK2 activation.
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PMID:Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor. 902 17

RAFTK, a novel nonreceptor protein kinase, has been shown to be involved in focal adhesion signal transduction pathways in neuronal PC12 cells, megakaryocytes, platelets, and T cells. Because focal adhesions may modulate cytoskeletal functions and thereby alter phagocytosis, cell migration, and adhesion in monocyte-macrophages, we investigated the role of RAFTK signaling in these cells. RAFTK was abundantly expressed in THP1 monocytic cells as well as in primary alveolar and peripheral blood-derived macrophages. Colony-stimulating factor-1 (CSF-1)/macrophage colony-stimulating factor (M-CSF) stimulation of THP1 cells increased the tyrosine phosphorylation of RAFTK; similar increases in phosphorylation were also detected after lipopolysaccharide stimulation. RAFTK was phosphorylated with similar kinetics in THP1 cells and peripheral blood-derived macrophages. Immunoprecipitation analysis showed associations between RAFTK and the signaling molecule phosphatidylinositol-3 (PI-3) kinase. PI-3 kinase enzyme activity also coprecipitated with the RAFTK antibody, further confirming this association. The CSF-1/M-CSF receptor c-fms and RAFTK appeared to associate in response to CSF-1/M-CSF treatment of THP1 cells. Inhibition of RAFTK by a dominant-negative kinase mutant reduced CSF-1/M-CSF-induced MAPK activity. These data indicate that RAFTK participates in signal transduction pathways mediated by CSF-1/M-CSF, a cytokine that regulates monocyte-macrophage growth and function.
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PMID:The related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated and participates in colony-stimulating factor-1/macrophage colony-stimulating factor signaling in monocyte-macrophages. 957 36

Granulocyte-colony-stimulating factor (G-CSF), a hematopoietic cytokine, regulates the proliferation and differentiation of granulocytic progenitor cells and functionally activated mature neutrophils. G-CSF also affects nonhematopoietic tumor cells by the binding of G-CSF to its specific receptor (G-CSFR) on the cells. In this study, we investigated the effect of G-CSF on the invasive potential of head-and-neck carcinoma cells, and explored the intracellular events initiated by the binding of G-CSF in tumor cells. In vitro treatment of head-and-neck-carcinoma cell lines, IMC-2, IMC-3, KB, Ca9-22, SCCKN and SCCTF, with recombinant G-CSF (rG-CSF) significantly augmented their invasive potential in dose- and time-dependent manners. Among these cancer cells, IMC-2, IMC-3, KB and Ca9-22 cells produced little G-CSF, while large amounts of G-CSF were produced by SCCKN and SCCTF cell lines. Anti-G-CSF antibody (Ab) abrogated the rG-CSF-enhanced invasiveness to the control level of that in untreated cancer cell lines. Immunocytochemical staining and Western blotting using anti-G-CSFR monoclonal antibody (MAb) revealed the expression of G-CSFR on head-and-neck-cancer cell lines exhibiting the enhancement of invasive activity by rG-CSF. IMC-2 cells, having the highest invasive ability among the cell lines used, showed augmentation of G-CSFR expression on stimulation with rG-CSF. Furthermore, stimulation of IMC-2 cells with rG-CSF induced rapid activation of tyrosine-phosphorylated JAK1, suggesting that the G-CSF signal may be transduced into the cells through G-CSFR. Moreover, the gelatinolytic activity of IMC-2 cells was enhanced by stimulation of rG-CSF, and the enhanced invasiveness was inhibited on addition of the tissue inhibitors of metalloproteinases (TIMPs). These results suggest that exogenous rG-CSF may increase the risk of metastasis and/or local recurrence in patients with G-CSFR-positive head-and-neck squamous-cell carcinoma, via an invasive mechanism.
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PMID:Granulocyte-colony-stimulating factor enhances invasive potential of human head-and-neck-carcinoma cell lines. 993 35


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