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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone acts through binding to membrane receptors that belong to the cytokine receptor superfamily. Ligand binding induces receptor dimerization and activation of the receptor-associated kinase: JAK2; this results in phosphorylation of the kinase itself, of the receptor, and of many cellular proteins. Among these are the Stat proteins as well as adaptors leading to the activation of the Ras/MAP kinase pathway and of the PI-3 kinase pathway. Activation by growth hormone is very transient and several mechanisms are involved in this downregulation: internalization and degradation of the receptor and recruitment of phosphatases or of specific inhibitors of the JAK/Stat pathway, the SOCS proteins.
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PMID:Regulators of growth hormone signaling. 1071 37

Gab1 is a member of the Gab/DOS (Daughter of Sevenless) family of adapter molecules, which contain a pleckstrin homology (PH) domain and potential binding sites for SH2 and SH3 domains. Gab1 is tyrosine phosphorylated upon stimulation of various cytokines, growth factors, and antigen receptors in cell lines and interacts with signaling molecules, such as SHP-2 and phosphatidylinositol 3-kinase, although its biological roles have not yet been established. To reveal the functions of Gab1 in vivo, we generated mice lacking Gab1 by gene targeting. Gab1-deficient embryos died in utero and displayed developmental defects in the heart, placenta, and skin, which were similar to phenotypes observed in mice lacking signals of the hepatocyte growth factor/scatter factor, platelet-derived growth factor, and epidermal growth factor pathways. Consistent with these observations, extracellular signal-regulated kinase mitogen-activated protein (ERK MAP) kinases were activated at much lower levels in cells from Gab1-deficient embryos in response to these growth factors or to stimulation of the cytokine receptor gp130. These results indicate that Gab1 is a common player in a broad range of growth factor and cytokine signaling pathways linking ERK MAP kinase activation.
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PMID:Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. 1077 59

Recent studies have begun to elucidate the molecular actions of growth hormone, a major regulator of somatic growth and metabolic functions. The cell surface growth hormone receptor, a member of the cytokine receptor superfamily, binds as a dimer to a single growth hormone molecule. Receptor dimerization precedes signal transduction, which is predominantly mediated by the non-receptor tyrosine kinase, Jak2. Activation of Jak2 leads to mitogenic proliferation, phosphorylation of intracellular proteins, MAP kinase activation, activation of Stats 1, 3, and 5, and induction of target gene expression. Specific cytoplasmic domains of the growth hormone receptor mediate Jak2 activation, metabolic actions of growth hormone, Stat activation, and calcium influx.
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PMID:The molecular basis of growth hormone action. 1099 Apr 39

The common use of the cytokine receptor gp130 has served as an explanation for the extremely redundant biological activities exerted by interleukin (IL)-6-type cytokines. Indeed, hardly any differences in signal transduction initiated by these cytokines are known. In the present study, we demonstrate that oncostatin M (OSM), but not IL-6 or leukemia inhibitory factor, induces tyrosine phosphorylation of the Shc isoforms p52 and p66 and their association with Grb2. Concomitantly, OSM turns out to be a stronger activator of ERK1/2 MAPKs. Shc is recruited to the OSM receptor (OSMR), but not to gp130. Binding involves Tyr(861) of the OSMR, located within a consensus binding sequence for the Shc PTB domain. Moreover, Tyr(861) is essential for activation of ERK1/2 and for full activation of the alpha(2)-macroglobulin promoter, but not for an exclusively STAT-responsive promoter. This study therefore provides evidence for qualitative differential signaling mechanisms exerted by IL-6-type cytokines.
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PMID:Non-redundant signal transduction of interleukin-6-type cytokines. The adapter protein Shc is specifically recruited to rhe oncostatin M receptor. 1101 27

The cytokine receptor subunits gp130, leukemia inhibitory factor receptor alpha (LIFRalpha), and oncostatin M receptor beta (OSMRbeta) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by down-regulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFRalpha, and OSMRbeta by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFRalpha degradation is promoted by activated ERK and that degradation of gp130, OSMRbeta, and a fraction of LIFRalpha involves mechanisms that are separate from signal transduction. These mechanisms include ligand-mediated dimerization, internalization, and endosomal/lysosomal degradation. Proteosomal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding.
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PMID:Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. 1160 99

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.
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PMID:Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. 1171 37

The cytokine receptor common beta subunit (beta(c)) transmits intracellular signals upon binding ligand such as granulocyte-macrophage colony-stimulating factor or interleukin-3 (IL-3); however, transcriptional regulation under the control of signaling events downstream of the beta(c) is not fully understood. Using murine Ba/F3 cells, here we demonstrate that the beta(c)-mediated signals stimulate NF-kappa B-driven gene expression of not only the reporter construct but also endogenous target genes such as IL-6. Analyzing the effects of several inhibitors or mutant receptors revealed that this NF-kappa B activation is mediated neither by MEK/ERK/MAPK nor by the phosphatidylinositol 3-kinase pathway but by STAT5. Overexpression experiments of the wild-type or constitutive active form of STAT5 further confirmed this notion. In addition, STAT5-dependent NF-kappa B activation is mediated not through an inducible nuclear translocation but via up-regulation of both DNA binding activity and transactivation potential of NF-kappa B. Furthermore, we also show that as yet undefined humoral factor(s) may be involved in this NF-kappa B activation process. Taken together, we may propose that cytokine receptor-mediated STAT5 activation and expression of its target genes culminates in a unique mode of NF-kappa B activation and gene expression.
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PMID:Cytokine receptor common beta subunit-mediated STAT5 activation confers NF-kappa B activation in murine proB cell line Ba/F3 cells. 1174 13

Keratins 8 (K8) and 18 are the primary intermediate filaments of simple epithelia. Phosphorylation of keratins at specific sites affects their organization, assembly dynamics, and their interaction with signaling molecules. A number of keratin in vitro and in vivo phosphorylation sites have been identified. One example is K8 Ser-73, which has been implicated as an important phosphorylation site during mitosis, cell stress, and apoptosis. We show that K8 is strongly phosphorylated on Ser-73 upon stimulation of the pro-apoptotic cytokine receptor Fas/CD95/Apo-1 in HT-29 cells. Kinase assays showed that c-Jun N-terminal kinase (JNK) was also activated with activation kinetics corresponding to that of K8 phosphorylation. Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material. In addition, co-immunoprecipitation studies revealed that part of JNK is associated with K8 in vivo, correlating with decreased ability of JNK to phosphorylate the endogenous c-Jun. Taken together, K8 is a new cytoplasmic target for JNK in Fas receptor-mediated signaling. The functional significance of this phosphorylation could relate to regulation of JNK signaling and/or regulation of keratin dynamics.
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PMID:The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. 1178 24

In this study, we show that the G protein-coupled receptor agonist thrombin, the glycoprotein VI agonist convulxin, and the cytokine receptor Mpl agonist thrombopoietin (TPO) are able to induce activation of RAS in human platelets. Recruitment of GRB2 by tyrosine-phosphorylated proteins in response to TPO and convulxin but not by thrombin occurred with a similar time-course to RAS activation, consistent with a causal relationship. On the other hand, activation of ERK2 by thrombin and convulxin is delayed and also inhibited by the protein kinase C inhibitor Ro-31 8220, whereas RAS activation is unaffected. Further evidence for differential regulation of RAS and ERK is provided by the observations that TPO, which activates RAS but not protein kinase C, does not activate ERK, and that the inhibitor of SRC kinases PP1 inhibits activation of RAS but not ERK2 in response to thrombin. Our results demonstrate that activation of RAS is not necessarily coupled to ERK in human platelets.
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PMID:Regulation of RAS in human platelets. Evidence that activation of RAS is not sufficient to lead to ERK1-2 phosphorylation. 1187 66

Interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proapoptotic cytokines and by promoting expression of cell survival signals. Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways--including Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB--ultimately promoting cell survival by inhibiting both ligand- and mitochondrial-induced apoptotic pathways. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation. Finally, IL-10 induces anergy in brain-infiltrating T cells by inhibiting cell signaling through the costimulatory CD28-CD80/86 pathway. The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.
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PMID:Interleukin-10 in the brain. 1194 58


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