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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) and IGFs have a long distinguished history in diabetes, with possible participation in the development of renal complications. The implicated effect of GH in diabetic end-stage organ damage may be mediated by growth hormone receptor (GHR) or postreceptor events in GH signal transduction. The present study investigates the effects of diabetes induced by streptozotocin (STZ) on renal GH signaling. Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. Immunohistochemical studies show that GH-induced p-Akt and p-ERK activation is apparently more pronounced in the kidneys of diabetic rats. Administration of G120K-PEG, a GH antagonist, in diabetic mice shows inhibitory effects on diabetic renal enlargement and reverses the alterations in GH signal transduction observed in diabetic animals. The present study demonstrates a role for GH signaling in the pathogenesis of early diabetic renal changes and suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.
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PMID:Modulation of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist. 1208 60

The ets transcription factor, TEL, undergoes chromosomal rearrangements with the tyrosine kinase JAK2. TEL-JAK2 is constitutively active, confers cell line factor independence, and activates signal transducer and activator of transcription-1 (STAT1), STAT3, and STAT5. Data from bone marrow transplantation models suggest that STAT5 activation does not account for the entire disease phenotype induced by TEL-JAK2. This study examined additional signaling pathways that are activated by TEL-JAK2. TEL-JAK2 expression in Ba/F3 cells results in constitutive association and tyrosine phosphorylation of Shc and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2. Direct Grb2 recruitment is also possible because a putative Grb2 binding site, Tyr314, is present on TEL-JAK2(5-19) and TEL-JAK2(5-12). Studies with a TEL-JAK2(5-19)Tyr314Phe mutant support a role for Tyr314 in Grb2 recruitment, because Grb2 association with TEL-JAK2(5-19)Tyr314Phe is significantly reduced. Interestingly, TEL-JAK2(5-19)Tyr314Phe shows reduced Ras activation when compared with TEL-JAK2(4-17), TEL-JAK2(5-12), and TEL-JAK2(5-19). Analysis of extracellular signal-regulated kinase-1/2 (ERK1/2), stress-activated protein/Jun kinase (SAPK/JNK), and p38 demonstrates the activation of SAPK/JNK and phosphorylation of p38 by all TEL-JAK2 isoforms. TEL-JAK2(5-12) and TEL-JAK2(5-19) preferentially phosphorylate ERK2, whereas TEL-JAK2(4-17) phosphorylated ERK2 at lower levels. Inhibition studies demonstrated that ERK1/2 activation was necessary for Ba/F3 factor independence mediated by TEL-JAK2(5-19), while inhibition of SAPK/JNK or p38 activity had no effect. Our data reveal the requirement of ERK activation by TEL-JAK2(5-19) in Ba/F3 cells and suggest that TEL-JAK2 leukemogenic potential may be mediated in part through ERK1/2.
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PMID:TEL-JAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways. 1214 29

Secretion of growth hormone (GH) in adult male rats is characterized by high peak and undetectable trough levels, both of which are required for male-specific pattern of liver gene expression and GH-induced phosphorylation of STAT5. The present study suggests that regulation of GH receptor (GHR) levels in rat hepatoma cells by repeated GH stimulation determines GH responsiveness via the JAK2/STAT5 pathway. A short exposure to GH rapidly reduced GHR levels which resulted in an equal desensitization of the JAK2/STAT5 pathway. Recovery of GH-induced STAT5 phosphorylation correlated with the time-dependent recovery of GHR levels during incubation in the absence of GH. Acute GH also induced phosphorylation of ERK1/2 and Akt, and this induction was also inhibited by prior exposure to GH. However, unlike the JAK2/STAT5 pathway, the effect of GH to activate the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways did not recover following prolonged incubation in the absence of GH. Thus, GH administration desensitizes the JAK2/STAT5 pathway, possibly because of down-regulation of GHR, whereas an additional post-receptor mechanism is required for the prolonged refractoriness of the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways toward a second GH stimulation. Our study suggests that both receptor and post-receptor mechanisms are important in GH-induced homologous desensitization.
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PMID:Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation. 1216 50

Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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PMID:Structure-based design of novel anticancer agents. 1218 92

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.
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PMID:An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. 1220 10

Neuregulin-1 (NRG-1) is part of a family of proteins whose members are structurally related to epidermal growth factor. NRG-1 induces cell proliferation through a high-affinity receptor complex composed of a heterodimer of human epidermal growth factor-like receptor (HER) 2 and 3. In this study, we show that NRG-1 activates the Janus kinases (JAK) and signal transducer and activator of transcription proteins (STAT). NRG-1 induced a rapid and transient increase in tyrosine phosphorylation of TYK2 and JAK3, but not JAK1 or JAK2, and induced STAT3 and STAT5 tyrosine phosphorylation. Upon phosphorylation, STAT3 translocated to the nucleus within 1 h. Activation of the JAK-STAT pathway was dependent on HER2/HER3 heterodimerization and was necessary for NRG-1-induced proliferation. Inhibition of HER2's ability to dimerize using the HER2-specific antibody 2C4 completely blocked NRG-1-induced JAK3, TYK2, STAT3, and STAT5 tyrosine phosphorylation. Blocking the JAK-STAT pathway with a specific JAK-STAT pathway inhibitor, AG490, inhibited NRG-1-induced JAK and STAT phosphorylation and cell proliferation. These data suggest that NRG-1 activates the JAK-STAT signal transduction pathway through its high-affinity receptor, the HER2/HER3 heterodimer. This pathway plays an important role in NRG-1-stimulated proliferation of pulmonary epithelial cells.
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PMID:Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. 1220 92

We have demonstrated here that growth hormone (GH) stimulates the formation of the active GTP-bound form of both RalA and RalB in NIH-3T3 cells. Full activation of RalA and RalB by GH required the combined activity of c-Src and JAK2, both kinases activated by GH independent of the other. Activation of RalA and RalB by growth hormone did not require the activity of JAK2 per se. Ras was also activated by GH and was required for the GH-stimulated formation of GTP-bound RalA and RalB. Activation of RalA by GH subsequently resulted in increased phospholipase D activity and the formation of its metabolite, phosphatidic acid. GH-stimulated RalA-phospholipase D-dependent formation of phosphatidic acid was required for activation of p44/42 MAPK and subsequent Elk-1-mediated transcription stimulated by GH. Thus we report the identification of a JAK2-independent pathway regulating GH-stimulated p44/42 MAPK activity.
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PMID:Identification of a JAK2-independent pathway regulating growth hormone (GH)-stimulated p44/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent. 1221 45

Interleukin-3 (IL-3) is one of the cytokines of significance for the regulation of hematopoiesis and inflammation. Recently, we established IL-3-dependent Ba/F3 pro-B cells ectopically expressing RON tyrosine kinase, a receptor for macrophage-stimulating protein (MSP), and showed that MSP stimulation specifically promoted cell morphological changes through tyrosine phosphorylation of the IL-3 common beta-chain receptor subunit (betac) by activated RON kinase without activation of JAK2 tyrosine kinase. Here we investigate the IL-3 signaling pathway leading to morphological changes through tyrosine phosphorylation of betac. Treatment of RON-expressing cells with PD98059 or U0126, inhibitors of mitogen-activated protein kinase kinase activity, blocked both IL-3- and MSP-induced morphological changes. Upon stimulation with IL-3 or MSP, extracellular-regulated kinase (ERK) and F-actin were redistributed in uropod-like structures. ERK and F-actin were colocalized within uropod-like structures, and a majority of F-actin were localized around the peripheries of accumulated ERK. Tyrosine phosphorylation of ERK was detected after stimulation with IL-3 or MSP, whereas treatment with U0126 specifically inhibited IL-3- or MSP-induced ERK phosphorylation but not tyrosine phosphorylation of betac. These results suggest that the activation and localization of ERK to uropod-like structures play a role in IL-3-induced morphological changes.
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PMID:Redistribution of ERK/MAP kinase to uropod-like structures in interleukin-3-induced cell shape changes. 1227 May 48

Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation. STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the DNA binding of the STAT proteins. The mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2 proteins. In these conditions, the expression of cartilage-specific matrix genes, type II collagen, aggrecan core, and link proteins was found to be markedly down-regulated. This negative effect was abolished by addition of parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP kinases with PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These IL-6 effects might contribute to the phenotype loss of chondrocytes in joint diseases and the alteration of articular cartilage associated with this pathology.
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PMID:JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. 1241 23

We examined the mechanism by which interleukin (IL)-5 causes beta(2)-integrin adhesion of human eosinophils. IL-5 caused time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38alpha in eosinophils as detected by their phosphorylation. Preincubation of eosinophils with U0126, a mitogen-activated protein kinase/ERK kinase inhibitor, suppressed IL-5-induced activation of cytosolic phospholipase A(2) (cPLA(2)) and eosinophil adhesion, and p38 inhibition by SB203580 had neither effect. ERK1/2 phosphorylation and eosinophil adhesion were blocked by inhibition of the src-family tyrosine kinase, Janus tyrosine kinase (JAK)2, or phosphoinositide-3 kinase (PI3K). Coimmunoprecipitation assay demonstrated that Lyn, a src-family tyrosine kinase, was constitutively associated with PI3K. Inhibition of src-tyrosine kinase but not JAK2 suppressed PI3K activation. Our data suggest that IL-5 induces beta(2)-integrin adhesion of human eosinophils by regulation of cPLA(2) activation caused by ERK1/2 phosphorylation. This phosphorylation results from activation of PI3K and protein tyrosine kinases. We also find that src-family tyrosine kinase, possibly Lyn, is the upstream kinase causing PI3K activation.
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PMID:IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2. 1242 28


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