Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin receptors include a long form (OBRl) with 302 cytoplasmic residues that is presumed to mediate most or all of leptins signaling, and several short forms, including one (OBRs) that has 34 cytoplasmic residues, is widely expressed, and is presumed not to signal but to mediate transport or clearance of leptin. We studied the abilities of these two receptor isoforms to mediate signaling in transfected cells. In response to leptin, OBRl, but not OBRs, underwent tyrosine phosphorylation that was enhanced by co-expression with JAK2. In cells expressing receptors and JAK2, both OBRs and OBRl mediated leptin-dependent tyrosine phosphorylation of JAK2, and this was abolished with OBRs when the Box 1 motif was mutated. In cells expressing receptors, JAK2 and IRS-1, leptin induced tyrosine phosphorylation of IRS-1 through OBRs and OBRl. In COS cells expressing hemagglutinin-ERK1 and receptors, leptin increased ERK1 kinase activity through OBRl, with the magnitude increased by co-expression of JAK1 or JAK2, and to a lesser degree through OBRs, despite greater receptor expression. In stable Chinese hamster ovary cell lines expressing OBRs or OBRl, leptin stimulated endogenous ERK2 phosphorylation. Whereas leptin stimulated tyrosine phosphorylation of hemagglutinin-STAT3 and induction of a c-fos luciferase reporter plasmid through OBRl, OBRs was without effect in these assays. In conclusion, OBRl is capable of signaling to IRS-1 and mitogen-activated protein kinase via JAK, in addition to activating STAT pathways. Although substantially weaker than OBRl, OBRs is capable of mediating signal transduction via JAK, but these activities are of as yet unknown significance for leptin biology in vivo.
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PMID:Divergent signaling capacities of the long and short isoforms of the leptin receptor. 940 87

Guinea pig bone marrow megakaryocytes were isolated and cultured on collagen gels to promote proplatelet formation. In control cultures 15.6% of the cells formed proplatelets. Both IL6 and TPO stimulated dose dependent increases in the percent of proplatelet forming cells up to 26.7% at 100ng/mal IL6 and 26.8% at 100 ng/ml TPO. IL1 and IL3 had no effect on proplatelet formation. IL3 in combination with IL6 and TPO blocked the increase in proplatelet formation observed with IL6 or TPO alone. IL3 was also found to stimulate thymidine incorporation in megakaryocytes. The role of phosphorylation in proplatelet formation was studied using certain inhibitors. The tyrosine kinase inhibitor genestien had no effect on proplatelet formation at concentrations up to 100 microg/ml. The phosphatase inhibitors calyculin A and okadaic acid both inhibited proplatelet formation. Studies on protein phosphorylation revealed that IL6, but not TPO, stimulated phosphorylation of JAK1, JAK2 and MAP kinase. TPO did stimulate tyrosine phosphorylation of Tyk-2. Although IBMX stimulated proplatelet formation, it inhibited phosphorylation of JAK1 and MAP kinase. Adhesion of megakaryocytes to collagen gel also inhibited phosphorylation of JAK1 and JAK2, while MAP kinase phosphorylation was unaffected. These data show that IL6 and TPO stimulate megakaryocyte proplatelet formation. In addition, although these cytokines increase phosphorylation of signal transduction proteins in the JAK/STAT pathway, it appears that a different signal transduction pathway regulated by a combination of phosphatase activity and cAMP levels, leads to proplatelet formation.
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PMID:Effect of recombinant interleukin-6 and thrombopoietin on isolated guinea pig bone marrow megakaryocyte protein phosphorylation and proplatelet formation. 941 Apr 69

Leptin at 1-5 nM, the concentrations observed in obese subjects, caused an increase in the active form of mitogen-activated protein kinase (MAPK) that was accompanied by increased tyrosine phosphorylation of STAT-1 and STAT-3 in a mouse pancreatic beta cell line, MIN6. Leptin also increased DNA synthesis and cell viability in MIN6 cells based on the results of [3H]-thymidine incorporation and colorimetric MTT assay, respectively. The specific MAPK-inhibitor PD98059 blocked not only the MAPK activation but also the increment in DNA synthesis and cell viability caused by leptin. Thus, leptin stimulates both the MAPK and the Janus kinase (JAK)-STAT cascade as well as inducing proliferation through the MAPK cascade in MIN6 cells. This mechanism might account, at least in part, for obesity-induced pancreatic islet hypertrophy.
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PMID:Leptin induces proliferation of pancreatic beta cell line MIN6 through activation of mitogen-activated protein kinase. 943 83

Hepatocyte growth factor (HGF) induces a three-phase response leading to the formation of branched tubular structures in epithelial cells. The HGF receptor tyrosine kinase works through a Src homology (SH2) docking site that can activate several signalling pathways. The first phase of the response (scattering), which results from cytoskeletal reorganization, loss of intercellular junctions and cell migration, is dependent on phosphatidylinositol-3-OH kinase and Rac activation. The second phase (growth) requires stimulation of the Ras-MAP kinase cascade. Here we show that the third phase (tubulogenesis) is dependent on the STAT pathway. HGF stimulates recruitment of Stat-3 to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element SIE. Electroporation of a tyrosine-phosphorylated peptide, which interferes with both the association of STAT to the receptor and STAT dimerization, inhibits tubule formation in vitro without affecting either HGF-induced 'scattering' or growth. The same result is obtained using a specific 'decoy' oligonucleotide that prevents STAT from binding to DNA and affecting the expression of genes involved in cell-cycle regulation (c-fos and waf-1). Activation of signal transducers that directly control transcription is therefore required for morphogenesis.
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PMID:Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. 944 Jun 92

Growth hormone (GH) signaling requires activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2. JAK2 activation by GH is believed to facilitate initiation of various pathways including the Ras, mitogen-activated protein kinase, STAT, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase systems. In the present study, we explore the biochemical and functional involvement of the Src homology 2 (SH2)-containing protein-tyrosine phosphatase, SHP-2, in GH signaling. GH stimulation of murine NIH 3T3-F442A fibroblasts, cells that homologously express GHRs, resulted in tyrosine phosphorylation of SHP-2. As assessed specifically by anti-SHP-2 coimmunoprecipitation and by affinity precipitation with a glutathione S-transferase fusion protein incorporating the SH2 domains of SHP-2, GH induced formation of a complex of tyrosine phosphoproteins including SHP-2, GHR, JAK2, and a glycoprotein with properties consistent with being a SIRP-alpha-like molecule. A reciprocal binding assay using IM-9 cells as a source of SHP-1 and SHP-2 revealed specific association of SHP-2 (but not SHP-1) with a glutathione S-transferase fusion incorporating GHR cytoplasmic domain residues 485-620, but only if the fusion was first rendered tyrosine-phosphorylated. GH-dependent tyrosine phosphorylation of SHP-2 was also observed in murine 32D cells (which lack IRS-1 and -2) stably transfected with the GHR. Further, GH-dependent anti-SHP-2 coimmunoprecipitation of the Grb2 adapter protein was detected in both 3T3-F442A and 32D-rGHR cells, indicating that biochemical involvement of SHP-2 in GH signaling may not require IRS-1 or -2. Finally, GH-induced transactivation of a c-Fos enhancer-driven luciferase reporter in GHR- and JAK2-transfected COS-7 cells was significantly reduced when a catalytically inactive SHP-2 mutant (but not wild-type SHP-2) was coexpressed; in contrast, expression of a catalytically inactive SHP-1 mutant allowed modestly enhanced GH-induced transactivation of the reporter in comparison with that found with expression of wild-type SHP-1. Collectively, these biochemical and functional data imply a positive role for SHP-2 in GH signaling.
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PMID:Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. 944 80

Eosinophils are potent effector cells contributing to allergic inflammation and asthma. The differentiation, recruitment, and effector functions of eosinophils are greatly affected by interleukin (IL)-5. In the eosinophil, signal transduction pathways including Jak-STAT and Ras-Raf-MAP kinase are stimulated by IL-5 and enzymatic activation of tyrosine kinases Jak-2 and Lyn has been demonstrated. The participation of adapter proteins in the responses of the Ras-Raf-MAP kinase pathway has been documented in many cytokine family receptors but the expression and activation of these proteins have not been demonstrated in eosinophils. In these studies, we have found three isoforms of the adapter protein, Shc, to be expressed in eosinophils. One of these isoforms, p52 Shc, was tyrosine phosphorylated following IL-5 treatment of eosinophils. A second adapter protein, Grb2, coimmunoprecipitated with Shc following IL-5 stimulation of eosinophils. Furthermore, p52 Shc was increasingly associated with a cell fraction resistant to detergent solubilization, following IL-5 administration. This cell fraction of limited detergent solubility is a complex mixture of proteins and the adapter protein Grb2, the tyrosine kinases Jak-2 and Lyn, the nucleotide exchange factor Vav, and the serine-threonine kinases p45 MAP kinase, Raf-1, and PKCbeta, were distributed either wholly or partially in the same fraction, as were the cytoskeletal proteins actin and vimentin. Only p52 Shc, however, demonstrated discernibly increased association with this fraction following IL-5 stimulation of eosinophils. These data suggest that IL-5 activates a signal transduction pathway utilizing the adapter proteins Shc and Grb2 in the human eosinophil.
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PMID:Interleukin 5 signals through Shc and Grb2 in human eosinophils. 944 48

Cytokine-mediated inhibition of eosinophil apoptosis is a mechanism causing tissue eosinophilia. Previously published work suggested that activation of the Lyn-Ras-Raf-1-MAP kinase pathway is obligatory for prevention of eosinophil apoptosis by eosinophil hematopoietins. We demonstrate herein that activation of freshly isolated human blood eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased tyrosine phosphorylation of Jak2. The tyrosine kinase blocker, tyrphostin B42, prevented activation of Jak2 but not Lyn, suggesting that Jak2 is the specific target for tyrphostin B42 in eosinophils. In addition, since Lyn remained unaffected by tyrphostin B42, it is unlikely that Jak2 is required for Lyn activation in this model. To test whether tyrosine phosphorylation of Jak2 is linked to GM-CSF-mediated prolonged eosinophil survival, we determined the effect of tyrphostin B42 on eosinophil viability and apoptosis. Prevention of Jak2 activation by tyrphostin B42 was associated with the inability of GM-CSF to prevent eosinophil apoptosis. These data suggest that disruption of not only the Lyn-Ras-Raf-1-MAP kinase but also the Jak-STAT pathway blocks the ability of eosinophil survival factors to prevent apoptosis in eosinophils.
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PMID:Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. 946 45

Ten years have passed since the molecular cloning of interleukin 6 (IL-6) in 1986. IL-6 is a typical cytokine, exhibiting functional pleiotropy and redundancy. IL-6 is involved in the immune response, inflammation, and hematopoiesis. The IL-6 receptor consists of an IL-6 binding alpha chain and a signal transducer, gp130, which is shared among the receptors for the IL-6 related cytokine subfamily. The sharing of a receptor subunit is a general feature of cytokine receptors and provides the molecular basis for the functional redundancy of cytokines. JAK tyrosine kinase is a key molecule that can initiate multiple signal-transduction pathways by inducing the tyrosine-phosphorylation of the cytokine receptor, gp130 in the case of IL-6, on which several signaling molecules are recruited, including STAT, a signal transducer and activator of transcription, and SHP-2, which links to the Ras-MAP kinase pathway. JAK can also directly activate signaling molecules such as STAT and Tec. These multiple signal-transduction pathways intimately regulate the expression of several genes including c-myc, c-myb, junB, IRF1, egr-1, and bcl-2, leading to the induction of cell growth, differentiation, and survival. The deregulated expression of IL-6 and its receptor is involved in a variety of diseases.
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PMID:Interleukin 6 and its receptor: ten years later. 950 91

One facet of cytokine receptor signaling involves the activation of signal transducers and activators of transcription (STATs). STATs are rapidly activated via tyrosine phosphorylation by Janus kinase (JAK) family members and subsequently inactivated within a short period. We investigated the effect of proteasome inhibition on interleukin-3 (IL-3) activation of the JAK/STAT pathway following stimulation of Ba/F3 cells. Treatment of Ba/F3 cells with the proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-3 receptor, beta common (betac), and STAT5 following stimulation. The effects of LLnL were not restricted to the JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK) phosphorylation were also prolonged in LLnL-treated cells. Further investigation showed these stable phosphorylation events were the result of prolonged activation of JAK2 and JAK1. These observations were confirmed using pharmacologic inhibitors. In the presence of LLnL, stable phosphorylation of STAT5 and betac was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on STAT5 phosphorylation could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting phosphorylated STAT5 could be stabilized by phosphatase, but not by proteasome inhibition per se. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the JAK/STAT pathway by regulating the deactivation of JAK.
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PMID:Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. 955 73

Through the cloning of two transcription factors named NF-IL6 and STAT3/APRF, two types of IL-6 signal transduction pathways from the cell surface to the nucleus have been revealed. NF-IL6 is phosphorylated and activated by a Ras-dependent MAP kinase cascade, while STAT3/APRF is directly tyrosine-phosphorylated by JAK kinases that associate with the cytoplasmic portion of the receptor, and translocates to the nucleus and activates transcription (JAK-STAT pathway). STAT3 is also tyrosine phosphorylated in response to epidermal growth factor (EGF), granulocyte colony-stimulating factor (G-CSF), leptin and other IL-6-type cytokines including ciliary neurotrophic factor (CNTF), oncostatin M and leukemia inhibitory factor (LIF). Mice deficient in the genes for NF-IL6 and STAT3 were generated. NF-IL6 mice were highly susceptible to facultative intracellular bacteria owing to ineffective killing of the pathogens by the macrophages. Futhermore, the tumor cytotoxicity of macrophages from NF-IL6 KO mice was severely impaired. These results demonstrate a crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities. The target disruption of STAT3 resulted in embryonic lethality prior to gastrulation, demonstrating that STAT3 is essential for the early development of mouse embryos.
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PMID:IL-6-regulated transcription factors. 957 Jan 35


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