Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncostatin M (OSM) is a 28-kD glycoprotein recently identified as a growth factor for human multiple myeloma cells. It belongs to a family of distantly related cytokines that includes interleukin 6, ciliary neurotrophic factor, leukemia-inhibitory factor, and interleukin 11. These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components. Such dimerization in turn activates receptor-associated tyrosine kinases. In the present study using U266B1 human multiple myeloma cells, we show that OSM induces tyrosine phosphorylation and activation of JAK2, but not JAK1 or Tyk2, kinases. The results also demonstrate that OSM induces direct interaction of JAK2 kinase with Grb2, an SH2/SH3 domain containing adaptor protein. The SH2 domain of Grb2 is directly associated with tyrosine-phosphorylated JAK2. Furthermore, the presence of Sos in the JAK2-Grb2 complex suggests a role for Ras in OSM-transduced signaling.
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PMID:Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. 750 25

Protein tyrosine phosphorylation and thus dephosphorylation are part of the interleukin (IL)-11 response in mouse 3T3-L1 cells. We report here for the first time the involvement and interactions of the SH2-containing protein tyrosine phosphatase Syp in the IL-11 signal transduction pathway. Addition of IL-11 to 3T3-L1 cells resulted in an increase in the tyrosine phosphorylation of Syp. When cell lysates were precipitated with glutathione S-transferase fusion products of Syp, the C-terminal SH2 domain of Syp was shown to precipitate several proteins of 70, 130, 150, and 200 kDa that were tyrosine phosphorylated in response to IL-11. Reciprocal immunoprecipitation experiments showed that Syp was inducibly associated with both gp130 and Janus kinase 2 (JAK2). A phosphopeptide containing the sequence for a potential Syp binding site (YXXV) was used to compete with the associations of Syp with gp130 and JAK2. The phosphopeptide reduced the Syp association with both gp130 and JAK2. To summarize, Syp has multiple interactions in IL-11 signal transduction. In addition to the IL-11-induced tyrosine phosphorylation of Syp, Syp coprecipitated with gp130, JAK2, and other tyrosine-phosphorylated proteins in response to IL-11. These findings may have extensive significance to IL-11 and related cytokine signal transduction, suggesting new pathways and mechanisms.
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PMID:Syp associates with gp130 and Janus kinase 2 in response to interleukin-11 in 3T3-L1 mouse preadipocytes. 755 3

The interleukin 6 receptor-associated signal transducer, gp130, is shared by receptor complexes for leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and interleukin 11. We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization. JAK1 is also tyrosine phosphorylated, but to a lesser extent, under the same conditions. Comparable results are obtained with hemopoietic lineage cells such as myeloid leukemic M1 cells and pro-B-cell line-derived transfectants expressing gp130, the former of which differentiate into macrophages after stimulation of gp130 and the latter of which initiate DNA synthesis. gp130-dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay. Deletion or point mutation in the membrane-proximal cytoplasmic motifs in gp130 that are conserved in the hemopoietic cytokine receptor family results in the loss of tyrosine phosphorylation of JAK2, which coincides with the lack of signal transducing capability of gp130 mutants.
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PMID:Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. 813 89

Recently, the ligand for the Mpl receptor (ML) was identified to be thrombopoietin, the principal regulator of megakaryocytopoiesis and thrombopoiesis. We examined the effects of ML, as a single factor or in combinations with early acting factors such as steel factor (SF), interleukin (IL)-3, IL-1, IL-6, and granulocyte colony-stimulating factor (G-CSF), on colony formation from primitive progenitors of mice. Cells enriched for cell cycle dormant primitive progenitors were isolated from bone marrow cells of 5-fluorouracil (5-FU)-treated mice by a combination of Nycodenz density gradient separation, immunomagnetic selection for lineage-negative cells, and fluorescence-activated cell sorter (FACS) sorting for Ly-6A/E+Kit+ cells. ML, in the presence of erythropoietin, could support the formation of only a few megakaryocyte colonies. However, ML acted synergistically with SF or IL-3 to support the formation of multiple types of hematopoietic colonies including multilineage colonies. Effects of the combination of ML and SF on multipotential progenitors were not mediated through other cells, as demonstrated by micromanipulation of individual progenitors. In suspension culture, the combination of ML and SF increased the number of multipotential progenitors. ML also acted synergistically with IL-11, IL-6, or G-CSF to support colony formation in serum-containing, but not in serum-free, cultures. However, the multilineage colony formation seen in serum-containing culture was completely abrogated by addition of ACK2, a neutralizing antibody to Kit protein. Serial observation (mapping studies) of colony development from multipotential progenitors suggested that ML triggers the cell division of dormant progenitors. Based on these observations, we propose that ML can function as an early acting cytokine and stimulate the proliferation of cell cycle dormant progenitors by shortening their G0 period.
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PMID:Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice. 863 22

Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction. This novel finding of JAK2/PP2A binding and release may have relevance to many serine/threonine regulated mechanisms such as P13K, Stat, and MAPK activation. These associations support a model of JAK2 as a protein kinase docking protein of IL-11 signal transduction that may be applicable to other gp130 and JAK signal transduction systems.
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PMID:Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11. 870 85

CD34+ and CD34+ DR- cells from the bone marrow (BM) of chronic-phase chronic myelogenous leukaemia (CML) patients at diagnosis were tested for their colony-forming ability in response to early and intermediate-late colony stimulating factors (CSFs). Molecular analysis revealed that 55.6+/-9% SD of CD 34+ DR- colonies, in which actin and ABL mRNA were detectable, expressed the product of the BCR-ABL gene. The percentage and the clonogenic efficiency of CML DR- cells were significantly lower than those of comparable DR- cells from normal donors. However, clonogenic assays using recombinant human CSFs demonstrated a remarkable proliferation of CML cells when stimulated by SCF, IL-11 and IL-3, used as single factors in the presence of erythropoietin (EPO) and was almost entirely due to erythroid progenitors. Conversely, optimal stimulation of CD34 +DR- cells from normal donors required co-incubation with three or more CSFs. Stroma-noncontact long-term cultures were then established in the presence of exogenous CSFs and human irradiated allogeneic stromal layers or the murine stromal cell line M2-10B4, engineered to produce G-CSF and IL-3. In these cultures the combination of SCF and IL-3 induced a 25.4 +/- 5 SD, 40 +/- 6 SD and 20.5 +/- 6 SD fold increase of colony-forming unit cells (CFU-C), at weeks 2, 4 and 5, respectively. At the same time-points the number of primitive long-term culture initiating cells (LTC-IC) showed a 4 +/- 2 SD, 3.3 +/- 1.5 SD and 2.3 +/-1 SD fold increase compared to baseline values. BCR-ABL mRNA analysis of single colonies demonstrated that 27 +/- 9% SD and 7 +/- 3% SD CFU-C at weeks 4 and 5, respectively, expressed the fusion gene, whereas leukaemic LTC-IC disappeared from the culture by week 2. These results suggest that leukaemic CD34+ DR- cells have a different pattern of response to CSFs than normal cells. In addition, we established culture conditions which allow selective expansion of benign haemopoietic cells coexisting with leukaemic progenitors.
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PMID:Selective expansion of normal haemopoietic progenitors from chronic myelogenous leukaemia marrow. 957 92

Previously, we showed that the JAK/STAT pathway was activated in pressure-overloaded rat heart, and that angiotensin II was partially involved in this activation. The present study was designed to investigate whether gp130-mediated signaling is involved in this activation, and if so, which interleukin (IL)-6 family cytokine is involved. Pressure overload was produced by ligation of the abdominal aorta of Wistar rats or ICR mice. IP-Western blot was performed to detect tyrosine phosphorylation of STATs, gp130, and the association of gp130 with JAK kinases. The serum concentration of IL-6 was measured by enzyme-linked immunosorbent assay. Expression of IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1) mRNA was quantitated. After pressure overload, rapid phosphorylation of STAT1 and STAT3 was observed at 5 min, STAT1 was rephosphorylated at 60 min, and intense phosphorylation of STAT3 was observed at 60 min. Both the phosphorylation of gp130 and the association of gp130 with JAK1 and JAK2 were increased after pressure overload. IL-6 was significantly increased by two-fold in the pressure-overloaded rats. Only CT-1 mRNA expression could be detected by Northern blot, and it increased after pressure overload. Reverse transcription-polymerase chain reaction revealed that IL-6 mRNA expression was increased 9.5-fold. IL-11, LIF, CNTF, and OSM expression were unaffected by pressure overload. These results suggested that gp130-mediated signaling was involved in the pressure overload-induced activation of the JAK/STAT pathway, and that IL-6 and CT-1 might be involved in this activation.
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PMID:Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. 1044 2

The function of the lung is dependent upon differentiation and proliferation of respiratory epithelial cells and the synthesis/secretion of surfactant lipids and proteins into air space. During the respiratory inflammatory response, cytokines produced by macrophages and epithelial cells in the respiratory system have significant influence on surfactant protein homeostasis. We report here that among family members of Janus family tyrosine kinase (JAK) and signal transducers and activators of transcription (STAT), only JAK 1 and STAT3 stimulated the -500 to +41 promoter activity of the surfactant protein B (SP-B) gene in respiratory epithelial cells. JAK1 and STAT3 were co-localized in alveolar type II epithelial cells where SP-B is synthesized and secreted. Interleukin 6 and interleukin 11, known to activate STAT3 synergistically, stimulated the SP-B promoter activity with retinoic acid, which is at least partially mediated through interactions between STAT3 and retinoid nuclear receptor enhanceosome proteins in pulmonary epithelial cells.
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PMID:Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells. 1178 90

Oncostatin M (OSM) is a glycoprotein cytokine that is produced by activated T-lymphocytes, monocytes, and macrophages. In a DNA synthesis assay, OSM reduced tritiated thymidine incorporation by 53% in Calu-1 lung carcinoma cells. Radiolabeled cDNAs from untreated Calu-1 cells and 30-h OSM-treated cells were used to probe duplicate nylon membrane cDNA expression arrays. This study revealed OSM-mediated expression of mRNAs encoding tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). Northern blot analysis showed that the steady-state level of tPA mRNA is nearly undetectable in Calu-1 cells. Exposure of these cells to OSM for 30 h increased tPA mRNA expression by 20-fold and PAI-1 mRNA expression by 5-fold. Exposure of these cells to other gp130 receptor family cytokines, including leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and IL-11, do not significantly affect DNA synthesis or induction of tPA/PAI-1. Western blot studies demonstrated that OSM mediates a marked increase in secretion of the tPA protein. Secreted tPA was present in the conditioned medium almost exclusively as tPA/PAI-1 complexes. Inhibitor studies demonstrated that OSM-mediated induction of tPA and PAI-1 mRNAs is largely dependent upon activation of the MEK1/2 pathway. The JAK3/STAT3 pathway potentially serves a secondary role in these regulatory events.
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PMID:Oncostatin M induces tissue-type plasminogen activator and plasminogen activator inhibitor-1 in Calu-1 lung carcinoma cells. 1209 Jul 57

IL-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production, and growth of certain types of tumor cells. Its excessive production plays a major role in pathogenesis of multiple myeloma and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline B, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2/STAT3. In a dose-dependent manner [(3)H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17beta-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.
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PMID:Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130. 1241 53


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