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)

The purpose of this study was to investigate the frequency of expression of the erbB/HER family of growth factor receptors, their ligand heregulin, and the two different signaling pathways p38 and mitogen-activated protein kinase (MAPK), as well as the status of HER-2 phosphorylation in tumor specimens from patients with primary breast cancer. The level of expression of these proteins was measured by quantitative immunohistochemistry combined with microscope-based image analysis in paraffin-embedded breast cancer tissue from 35 patients. The frequency of expression was: EGFR (51%), HER-2 (54%), P-HER-2 (48%), HER-3 (48%), HER-4 (57%), heregulin (48%), p38 (17%), MAPK (48%). There was evidence of associations among the coexpression of heregulin, EGFR, HER-2, and HER-3. Also, there was evidence of a positive association between P-MAPK and HER-4. HER-3 was expressed at high levels in patients younger than 50 years of age. There was a trend for expression of higher levels of HER-4 in tumors larger than 2 cm. The expression of EGFR, HER-2, heregulin, p38 and MAPK was independent of age, tumor size, number of lymph nodes involved or hormone receptor status. The HER family of growth factor receptors appear to be regulated independently in invasive breast cancer. Assessing the expression of multiple tumor markers by quantitative immuno-histochemistry is feasible. Further research is needed to determine the prognostic and predictive roles of the various associations between HER receptors, their ligands and signal transduction molecules in patients with early-stage breast cancer.
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PMID:Expression of erbB/HER receptors, heregulin and P38 in primary breast cancer using quantitative immunohistochemistry. 1169 42

The four receptor tyrosine kinases of the ErbB family play essential roles in several physiological processes and have also been implicated in tumor generation and/or progression. Activation of ErbB1/EGFR is mainly triggered by epidermal growth factor (EGF) and other related ligands, while activation of ErbB2, ErbB3, and ErbB4 receptors occurs by binding to another set of EGF-like ligands termed neuregulins (NRGs). Here we show that the Erk5 mitogen-activated protein kinase (MAPK) pathway participates in NRG signal transduction. In MCF7 cells, NRG activated Erk5 in a time- and dose-dependent fashion. The action of NRG on Erk5 was dependent on the kinase activity of ErbB receptors but was independent of Ras. Expression in MCF7 cells of a dominant negative form of Erk5 resulted in a significant decrease in NRG-induced proliferation of MCF7 cells. Analysis of Erk5 in several human tumor cell lines indicated that a constitutively active form of this kinase was present in the BT474 and SKBR3 cell lines, which also expressed activated forms of ErbB2, ErbB3, and ErbB4. Treatments aimed at decreasing the activity of these receptors caused Erk5 inactivation, indicating that the active form of Erk5 present in BT474 and SKBR3 cells was due to a persistent positive stimulus originating at the ErbB receptors. In BT474 cells expression of the dominant negative form of Erk5 resulted in reduced proliferation, indicating that in these cells Erk5 was also involved in the control of proliferation. Taken together, these results suggest that Erk5 may play a role in the regulation of cell proliferation by NRG receptors and indicate that constitutively active NRG receptors may induce proliferative responses in cancer cells through this MAPK pathway.
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PMID:Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. 1173 40

Overexpression of the growth factor receptors EGFR and erbB2 occurs frequently in several human cancers and is associated with aggressive tumour behaviour and poor patient prognosis. We have investigated the effects of ZD1839 (Iressa), a novel EGFR tyrosine kinase inhibitor, on the growth, in vitro and in vivo, of human cancer cell lines expressing various levels of EGFR and erbB2. Proliferation of EGFR-overexpressing A431 and MDA-MB-231 cells in vitro was potently inhibited (50%-70%) by ZD1839 with half-maximally effective doses in the low nanomolar range. In parallel, ZD1839 blocked autophosphorylation of EGFR and prevented activation of PLC-gamma 1, ERK MAP kinases and PKB/Akt by EGF. It also inhibited proliferation in EGFR(+) cancer cell lines overexpressing erbB2 (SKBr3, SKOV3, BT474) by between 20% and 80%, effects which correlated with inhibition of EGF-dependent erbB2 phosphorylation and activation of ERK MAP kinase and PKB/Akt in SKOV3 cells. Oral administration of ZD1839 inhibited the growth of MDA-MB-231 and SKOV3 tumours, established as xenografts in athymic mice, by 71% and 32%, respectively. Growth inhibition coincided with reduced proliferation but no change in apoptotic index. Collectively, these results show that ZD1839, at the doses studied, is a potent inhibitor of proliferation not only in cells overexpressing EGFR but also in EGFR(+) cells that overexpress erbB2.
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PMID:ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. 1174 77

Trophic mechanisms in which neighboring cells mutually control their survival by secreting extracellular factors play an important role in determining cell number. However, how trophic signaling suppresses cell death is still poorly understood. We now show that the survival of a subset of midline glia cells in Drosophila depends upon direct suppression of the proapoptotic protein HID via the EGF receptor/RAS/MAPK pathway. The TGFalpha-like ligand SPITZ is activated in the neurons, and glial cells compete for limited amounts of secreted SPITZ to survive. In midline glia that fail to activate the EGFR pathway, HID induces apoptosis by blocking a caspase inhibitor, Diap1. Therefore, a direct pathway linking a specific extracellular survival factor with a caspase-based death program has been established.
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PMID:Regulation of cell number by MAPK-dependent control of apoptosis: a mechanism for trophic survival signaling. 1183 42

We have investigated EGF-driven signaling processes in rat intestinal epithelial cell lines that overexpress either the alpha5beta1 integrin or the alpha2beta1 integrin. Both cell types display efficient activation of Erk/MAP kinase, but only the alpha5beta1 expressing cells display a strong activation of Akt. A complex is formed between activated EGFR and alpha5beta1, but not with alpha2beta1; this complex also contains ErbB3 and p85. Thus alpha5beta1 can support efficient activation of both the Erk and the phosphatidylinositol-3-kinase/Akt branches of the EGFR signaling cascade, whereas alpha2beta1 can support only the Erk branch.
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PMID:The alpha5beta1 integrin selectively enhances epidermal growth factor signaling to the phosphatidylinositol-3-kinase/Akt pathway in intestinal epithelial cells. 1185 76

We showed previously that epithelial growth factor (EGF) receptor (EGFR) signaling is triggered by metallic compounds associated with ambient air particles. Specifically, we demonstrated that As, Zn, and V activated the EGFR tyrosine kinase and the downstream kinases MEK1/2 and ERK1/2. In this study, we examined the role of Ras in EGFR signaling and the nuclear factor-kappaB (NF-kappaB) activation pathway and the possible interaction between these two signaling pathways in a human airway epithelial cell line (BEAS-2B) exposed to As, V, or Zn ions. Each metal significantly increased Ras activity, and this effect was inhibited by the EGFR tyrosine kinase activity inhibitor PD-153035. Adenoviral-mediated overexpression of a dominant-negative mutant form of Ras(N17) significantly blocked MEK1/2 or ERK1/2 phosphorylation in As-, Zn-, or V-exposed BEAS-2B cells but caused little inhibition of V-, Zn- or EGF-induced EGFR tyrosine phosphorylation. This confirmed Ras as an important intermediate effector in EGFR signaling. Interestingly, V, but not As, Zn, or EGF, induced IkappaBalpha serine phosphorylation, IkappaBalpha breakdown, and NF-kappaB DNA binding. Moreover, PD-153035 and overexpression of Ras(N17) each significantly blocked V-induced IkappaBalpha breakdown and NF-kappaB activation, while inhibition of MEK activity with PD-98059 failed to do so. In summary, exposure to As, Zn, and V initiated EGFR signaling and Ras-dependent activation of MEK1/2 and ERK1/2, but only V induced Ras-dependent NF-kappaB nuclear translocation. EGFR signaling appears to cross talk with NF-kappaB signaling at the level of Ras, but additional signals appear necessary for NF-kappaB activation. Together, these data suggest that, in V-treated BEAS-2B cells, Ras-dependent signaling is essential, but not sufficient, for activation of NF-kappaB.
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PMID:Role of Ras in metal-induced EGF receptor signaling and NF-kappaB activation in human airway epithelial cells. 1194 69

During the initial stage of Friend virus-induced erythroleukemia in mice, interaction of the viral protein gp55 with the erythropoietin receptor, and other host factors, drives the expansion of erythroid precursor cells. Recently, we demonstrated that the Friend virus susceptibility locus, Fv2, which is required for the expansion of infected cells, encodes a naturally occurring, N-terminally truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Here we show that in vitro expression of Sf-Stk confers Friend virus sensitivity to erythroid progenitor cells from Fv2(rr) mice. Furthermore, our data reveal that Sf-Stk kinase activity and Y436, but not Y429, are required for Epo-independent colony formation following Friend virus infection. Introduction of a mutation that results in failure to bind Grb2 abrogates the ability of Sf-Stk to induce colonies in response to Friend virus, while the Grb2 binding site from EGFR restores this response. Consistent with the ability of Grb2 to recruit SOS and Gab1, the Ras/MAPK and PI3K pathways are activated by Sf-Stk, and both of these pathways are required for gp55-mediated erythroblast proliferation. These data clearly demonstrate a requirement for signaling through Sf-Stk in the Epo-independent expansion of Friend virus-infected cells, and suggest a pivotal role for Grb2 in this response.
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PMID:Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus. 1203 58

The lipid growth factor lysophosphatidic acid (LPA) elicits multiple cellular responses, including cell growth and survival. LPA acts upon target cells by activating its cognate receptors, which belong to the G protein-coupled endothelial differentiation gene (EDG) family. To date, three known LPA receptors, termed LPA1, LPA2 and LPA3, have been molecularly characterized and cloned. Here, we review recent data describing the molecular steps involved in the LPA receptor-mediated activation of mitogenic extracellular signal-regulated kinase (ERK) pathway in prostate cancer. Induction of ERK by LPA proceeds via Gbetagamma-dependent activation of tyrosine kinases, including the epidermal growth factor (EGF) receptor and c-Src. Further, LPA-induced ERK activation involves matrix metalloproteinases (MMPs), which cause the release of active EGFR ligands. Finally, we present data demonstrating a correlation between the mitogenic effects of LPA and expression of the lp(A1) gene in the prostate cancer cells.
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PMID:Mitogenic action of LPA in prostate. 1206 37

Environmental and occupational exposure to arsenic is associated with increased risk of skin, urinary bladder and respiratory tract cancers. Increasing evidence indicates that arsenic acts at the level of tumor promotion by modulating the signaling pathways responsible for cell growth. One of this pathways might include c-Src dependent EGFR and MAPK activation.
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PMID:Arsenic carcinogenicity: relevance of c-Src activation. 1216 44

c-erbB receptor signalling induces pleiotropic responses and influences several biological functions involved in the pathogenesis and progression of HNSCC. Aberrant expression of multiple c-erbB receptors and ligands is frequently observed in tumour cells. EGFR appears to be a dominant factor controlling the malignant phenotype in HNSCC at least in part via regulation of molecules involved in invasive and angio-/lymphangiogenic processes. Although c-erbB-2 is an orphan receptor, the formation of heterodimer complexes appears to be an important mechanism for inter-receptor activation and synergistic signal transduction. The roles of c-erbB-3 and c-erbB-4 in HNSCC progression are less clear. However, their ability to form heterodimers with other c-erbB family members enhances proliferation and invasion in HNSCC cells. At least two major downstream signalling pathways, MAPK and PI3K, are involved in the transcriptional regulation of proteases and cytokines implicated in invasion and angiogenesis. Studies using clinical specimens confirmed experimental data that co-operative signalling of c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Most therapeutic studies in HNSCC so far have focused on the strategies targeting of EGFR. Due to the complexity of the system both at the receptor and ligand levels and the integrated biological functions of the c-erbB family in HNSCC, the effect of combined c-erbB blockade (or their downstream signalling pathways) on HNSCC progression should be explored.
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PMID:The role of c-erbB receptors and ligands in head and neck squamous cell carcinoma. 1216 15


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