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)

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.
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PMID:Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts. 758 9

The identification of JAK2 as a growth hormone (GH) receptor-associated, GH-activated tyrosine kinase has established tyrosyl phosphorylation as a signaling mechanism for GH. In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts, GH-dependent tyrosyl phosphorylation of IRS-1 was detected by 1 min and at GH concentrations as low as 5 ng/ml (0.23 nM). Tyrosyl phosphorylation of IRS-1 was transient, with maximal stimulation detected at 30 min and diminished signal detected at 60 min. The ability of GH receptor (GHR) to transduce the signal for IRS-1 tyrosyl phosphorylation is mediated by the intracellular region of GHR between amino acids 295 and 380 by a mechanism not involving the two tyrosines in this region. This region of GHR is required for GH-dependent JAK2 association and activation (VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia inhibitory factor. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH, interferon-gamma, and leukemia inhibitory factor and in cells expressing different GHR mutants, provides evidence that IRS-1 may interact with JAK2 or an auxiliary molecule that binds to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well characterized insulin-like metabolic effects of GH observed in a variety of cell types.
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PMID:Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. 778 32

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

Interleukin-11 (IL-11) shares the common signal transducer gp130 with IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and triggers activation of unknown tyrosine kinases as the early steps of signal transduction pathway. Here we identify a 130-kilodalton tyrosine-phosphorylated protein induced by IL-11 in 3T3-L1 cells as JAK2 tyrosine kinase. We further show that the in vitro kinase activity of JAK2 is greatly enhanced following stimulation with IL-11 in 3T3-L1 cells and TF-1 cells. Furthermore, we demonstrate that JAK2 physically associates with the signal transducer gp130. Similar results were observed following stimulation with IL-6, LIF, and OSM. However, we were unable to show that JAK1 is tyrosine phosphorylated and activated by IL-11 under identical conditions. These results suggest that JAK2 tyrosine kinase is one of the tyrosine kinases involved in signal transduction mediated by IL-11, IL-6, LIF, and OSM.
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PMID:Identification of a 130-kilodalton tyrosine-phosphorylated protein induced by interleukin-11 as JAK2 tyrosine kinase, which associates with gp130 signal transducer. 817 77

A number of cytokines have been shown to exert their effects via a recently discovered signaling cascade. One step in this pathway is mediated by a family of nonreceptor protein tyrosine kinases, the Janus kinases or JAK kinases, which become phosphorylated upon ligand-receptor binding and receptor phosphorylation. This in turn is followed by phosphorylation of certain members of a family of latent transcription factors, called signal transducers and activators of transcription (STATs), which subsequently enter the nucleus, bind to DNA in a sequence-specific fashion, and modulate transcription. In view of the apparent role of leukemia inhibitory factor (LIF) in bone remodeling, we sought to determine which, if any, of the JAK/STAT family members are involved in mediating the actions of LIF using the MC3T3-E1 cell line (a spontaneously immortalized osteoblast) and normal murine calvarial osteoblasts. We report here rapid and transient phosphorylation of the LIF receptor, and similarly, we detect phosphorylation of predominantly JAK1 and to a minor extent JAK2 in response to LIF treatment in MC3T3-E1 cells. In these experiments we also detect phosphorylation of STAT1 and to a much lesser degree STAT3 upon addition of LIF. Phosphorylation of the STAT1 proteins correlates directly with their ability to bind DNA in a gel mobility shift assay in MC3T3-E1 and in normal calvarial osteoblasts. These studies suggest that LIF action in these cells, as in other cell types, is mediated in part via specific members of the JAK/STAT pathway.
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PMID:Leukemia inhibitory factor as a mediator of JAK/STAT activation in murine osteoblasts. 859 40

Oncostatin M (OSM) is a member of the interleukin-6 (IL6)-related cytokine subfamily that includes IL6, IL11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor and cardiotrophin-1. While human OSM has been characterized and the bovine OSM gene was recently cloned, the murine counterpart had not been identified. Here we describe molecular cloning of murine OSM as an immediate early gene induced by a subset of cytokines including IL2, IL3 and erythropoietin (EPO) in myeloid and lymphoid cell lines. The induction kinetics of OSM are rapid and transient, reaching a maximal level within 30-60 min and decreasing thereafter. Induction of OSM depends on the signals generated by the membrane-proximal region of the EPO receptor as well as that of the beta chain of the IL3/GM-CSF receptor, which activate JAK2 and STAT5. About 100 bases upstream of the transcription initiation site of the OSM gene contains a possible STAT5 binding site which is essential for IL2, IL3 and EPO-dependent promoter activity of the OSM gene. Expression of STAT5 and the EPO receptor in COS cells conferred EPO-dependent activation of the OSM promoter. Moreover, the mutant IL2 receptor lacking the ability to activate STAT5 induced c-myc but failed to induce OSM. Thus OSM is one of the common targets of a subset of cytokines that activate STAT5. The murine OSM gene is located near to the LIF gene, expressed at high levels in bone marrow and possesses similar biological activity to human OSM. Identification of murine OSM as a cytokine-inducible immediate early gene provides a new insight into the physiological function of this unique cytokine.
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PMID:Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway. 860 75

Oncastatin M (OSM) is one member of the leukemia inhibitory factor/interleukin-6 family of cytokines that has been shown to be a growth regulatory molecule. In osteoblastic cultures, OSM causes marked phenotypic changes and the enhanced secretion of interleukin-6. In this study, we have shown that stimulation of murine and human osteoblastic cultures and a human osteosarcoma cell line with OSM resulted in the tyrosine phosphorylation of a number of cellular proteins including members of both the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) family of signaling proteins. The JAKs, a family of intracellular kinases, and the STATs, a family of transcription factors, have both previously been shown to be tyrosine phosphorylated and activated in response to various cytokines, interferons, and growth factors in cells of non-skeletal origin. Using three different sources of cells of the osteoblast lineage, we demonstrate that OSM induces a rapid but transient tyrosine phosphorylation of the three JAK family members tested, JAK1, JAK2 and Tyk2. In addition, two members of the STAT family, Stat1alpha and Stat3, are tyrosine phosphorylated in osteoblastic cells in culture in response to OSM. OSM activation of this pathway in cells of the osteoblast lineage will result in the transcription of specific genes that ultimately may be associated with osteoblast function.
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PMID:Activation of the JAK-STAT signal transduction pathway by oncostatin-M cultured human and mouse osteoblastic cells. 862 84

GH has been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2 and the Src homology 2 domain-containing transcription factors Stats (signal transducers and activators of transcription) 1, 3, and 5. The present work investigates the role of GHR and JAK2 in the activation of Stats 1, 3, and 5 by GH. The ability of GH to stimulate the tyrosyl phosphorylation of these Stats was assessed in Chinese hamster ovary (CHO) cells expressing truncated and mutated GHR. GH was observed to stimulate tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHRs that bind JAK2 [GHR1-638 (full-length) and GHR1-454 (lacks approximately half of the cytoplasmic domain)] but not in CHO cells expressing GHR that do not bind JAK2 (GHR1-318 or GHR1-294). GH-dependent tyrosyl phosphorylation of Stat5, but not Stats 1 or 3, was reduced in CHO cells expressing GHR1-454. GH-dependent tyrosyl phosphorylation of Stats 3 and 5 was severely reduced and undetectable for Stat1 in cells expressing GHR1-454 in which tyrosines 333 and 338 (the only tyrosines phosphorylated within 1-454) are mutated to phenylalanine (GHR1-454Y333, 338F). However, GH-dependent phosphorylation of Stats 1, 3, and 5 was observed in cells expressing full-length GHR in which tyrosines 333 and 338 are mutated to phenylalanine (GHR1-638Y333, 338F) GH, whose receptor lacks previously defined Stat1- or Stat3-binding sites, was found in 3T3-F442A fibroblasts and 2fTGH-GHR cells to stimulate tyrosyl phosphorylation of JAK2 to a substantially greater extent than, and JAK1 to a similar extent as, leukemia inhibitory factor (LIF) and/or interferon gamma (IFN gamma), ligands whose receptors contains Stat3- and Stat1-binding sites and activate Stat3 and Stat1, respectively, better than GH. These findings suggest that: 1) JAK2 is required for GH-dependent phosphorylation of Stats 1, 3, and 5; 2) tyrosines 333 and/or 338 are required for maximal tyrosyl phosphorylation of Stats 1, 3, and 5; 3) Stat5 binds to a phosphorylated tyrosine(s) within amino acids 454-638 in addition to tyrosines 333 and/or 338; 4) GH stimulates tyrosyl phosphorylation of JAK1 in addition to JAK2 with JAK2 having a much greater response; 5) some Stat3 and Stat5 (and possibly Stat1) may bind to nonphosphorylated amino acids in GHR or to phosphorylated tyrosines in proteins that bind to GHR (e.g. JAK22) to be maximally activated; and 6) if JAK2, which contains Stat3-binding motifs, does serve as a docking site for some Stat proteins, Stat-JAK2 binding is likely to be more important for GH than LIF or IFN gamma in 3T3-F442A cells since GH induces 15 times more tyrosyl-phosphorylated JAK2 than LIF or IFN gamma.
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PMID:The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. 873 83

The fps/fes proto-oncogene encodes a cytoplasmic protein tyrosine kinase that is thought to participate in signaling pathways involving members of the cytokine receptor superfamily, including those for erythropoietin, granulocyte-macrophage colony-stimulating factor, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and interleukins 3, 4, 6, and 11. Expression of fps/fes has been detected in hematopoietic cells, vascular endothelial cells, and cell types arising from all three germ layers during early development. Here, we describe fps/fes expression in developing and adult tissues from normal mice or from transgenic animals overexpressing wild-type or activated mutant fps/fes alleles. The highest levels of fps/fes expression were seen in angioblasts of early yolk sac blood islands, chondrocytes, vascular endothelial cells, neuronal cells, and several epithelial cell types, including those of the choroid plexus and the uterus. Fps/Fes protein was concentrated in the perinuclear region of cultured neuronal, myeloid, epithelial, and vascular endothelial cells, and a chimeric Fps/Fes-green fluorescence protein colocalized with gamma-adaptin, a marker for the trans-Golgi apparatus. These observations suggest the involvement of Fps/Fes in vesicle transport processes in cells with prominent secretory functions.
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PMID:The fps/fes tyrosine kinase is expressed in myeloid, vascular endothelial, epithelial, and neuronal cells and is localized in the trans-golgi network. 880 11

In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately phosphorylated, with maximal phosphorylation detected at 15 min; the signal is substantially diminished by 60 min. In response to interferon-gamma, tyrosine phosphorylation of IRS-2 was prolonged, with substantial signal still detected at 60 min. Characterization of the mechanism of signaling utilized by GH indicated that tyrosine residues in GH receptor are not necessary for tyrosyl phosphorylation of IRS-2; however, the regions of GH receptor necessary for IRS-2 tyrosyl phosphorylation are the same as those required for JAK2 association and tyrosyl phosphorylation. The role of IRS-2 as a signaling molecule for GH is further demonstrated by the finding that GH stimulates association of IRS-2 with the 85-kDa regulatory subunit of phosphatidylinositol 3'-kinase and with the protein-tyrosine phosphatase SHP2. These results are consistent with the possibility that IRS-2 is a downstream signaling partner of multiple members of the cytokine family of receptors that activate JAK kinases.
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PMID:Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. 891 Jun 7


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