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)

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
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PMID:Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. 870 May 12

A collection of cell lines expressing each human epidermal growth factor receptor (HER) family member alone or in all pairwise combinations in a clone of NIH3T3 cells (3T3-7d) devoid of detectable epidermal growth factor receptor family members has been generated. Transformation, as measured by growth in soft agar, occurred only in the presence of appropriate ligand and only in cells expressing two different HER family members. Transfection of oncogenic neu (Tneu), conferred ligand-independent transformation only in cells which co-expressed HER1, HER3, or HER4, but not when expressed alone or with HER2. Cell lines were also tested for their ability to form tumors in animals. None of the cell lines expressing single HER family members was able to form tumors in animals with the exception of HER1, which was weakly tumorigenic. Although unable to form tumors when expressed alone, HER2 was tumorigenic when expressed with HER1 or HER3, but not HER4. Of all complexes analyzed, cells expressing HER1 + HER2 were the most aggressive. The relationship between HER1 activation, intracellular calcium fluxes, and phospholipase Cgamma1 activation is well established. We found that activation of HER1 was required for the induction of a calcium flux and the phosphorylation of phospholipase Cgamma1. These activities were independent of, and unaffected by, the co-expression of any other family member. Further, heregulin stimulation of all cell lines including those containing HER1 did not demonstrate any effect on intracellular calcium levels or phospholipase Cgamma1 phosphorylation. This demonstrates that heregulin induced cellular transformation by activating HER3- and HER4-containing complexes does not require the activation of either phospholipase Cgamma1 or the mobilization of intracellular calcium.
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PMID:The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells. 894 74

Cripto-1 (CR-1), a recently discovered protein of the epidermal growth factor (EGF) family, was found to interact with a high affinity, saturable binding site(s) on HC-11 mouse mammary epithelial cells and on several different human breast cancer cell lines. This receptor exhibits specificity for CR-1, since other EGF-related peptides including EGF, transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin, epiregulin, betacellulin, or heregulin beta1 that bind to either the EGF receptor or to other type 1 receptor tyrosine kinases such as erb B-3 or erb B-4 fail to compete for binding. Conversely, CR-1 was found not to directly bind to or to activate the tyrosine kinases associated with the EGFR, erb B-2, erb B-3, or erb B-4 either alone or in various pairwise combinations which have been ectopically expressed in Ba/F3 mouse pro-B lymphocyte cells. However, exogenous CR-1 could induce an increase in the tyrosine phosphorylation of 185- and 120-kDa proteins and a rapid (within 3-5 min) increase in the tyrosine phosphorylation of the SH2-containing adaptor proteins p66, p52, and p46 Shc in mouse mammary HC-11 epithelial cells and in human MDA-MB-453 and SKBr-3 breast cancer cells. CR-1 was also found to promote an increase in the association of the adaptor Grb2-guanine nucleotide exchange factor-mouse son of sevenless (mSOS) signaling complex with tyrosine-phosphorylated Shc in HC-11 cells. Finally, CR-1 was able to increase p42(erk-2) mitogen-activated protein kinase (MAPK) activity in HC-11 cells within 5-10 min of treatment. These data demonstrate that CR-1 can function through a receptor which activates intracellular components in the ras/raf/MEK/MAPK pathway.
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PMID:Cripto enhances the tyrosine phosphorylation of Shc and activates mitogen-activated protein kinase (MAPK) in mammary epithelial cells. 901 73

We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor-inducing activity. Three signal transducing transmembrane receptors for neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.
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PMID:Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. 910 49

Growth factor receptors of the epidermal growth factor (EGF) receptor family play pivotal roles in the regulation of cell proliferation and differentiation and are involved in the development of human cancers. It has been well documented that these receptors undergo growth factor-stimulated homo- and heterodimerization as a first step in the initiation of signaling cascades. Here we provide evidence for a new mechanism for growth factor-stimulated receptor dimer formation, designated secondary dimerization. The growth factor-induced dimerization and ensuing receptor trans-autophosphorylation results in the dissociation of the original (primary) receptor dimer. Each phosphorylated receptor monomer then interacts with a new (nonphosphorylated) receptor to form a secondary dimer. Treatment of cells with EGF yields Neu-ErbB3 secondary dimers, and heregulin treatment induces the formation of Neu-EGF receptor (secondary) dimers. The ability of EGF and heregulin to stimulate a cascade of dimerization events points to a novel mechanism by which multiple signaling activities and diverse biological responses are initiated by members of the EGF receptor family.
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PMID:Secondary dimerization between members of the epidermal growth factor receptor family. 911 72

The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-1 subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).
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PMID:ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis. 912 54

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent mitogen and chemotactic factor for fibroblasts, smooth muscle cells and keratinocytes. It is demonstrated that HB-EGF is not only a ligand for HER1, as previously reported, but for HER4 as well. HB-EGF binds to NIH 3T3 cells overexpressing either HER1 or HER4 alone, but not HER2 or HER3 alone. Binding to HER4 is independent of HER1. The ability of HB-EGF to bind to two different receptors is in contrast to EGF which binds to HER1, but not to HER4, and heregulin-beta1 which binds to HER4, but not to HER1. Besides binding, HB-EGF activates HER4. For example (i) it induces tyrosine phosphorylation of HER4 in cells overexpressing this receptor and of endogenous HER4 in MDA-MB-453 cells and astrocytes; (ii) it induces association of phosphatidylinositol 3-kinase (PI3-K) activity with HER4; and (iii) it is a potent chemotactic factor for cells overexpressing HER4. Chemotaxis is inhibited by wortmannin, a PI3-K inhibitor, suggesting a possible role for PI3-K in mediating HB-EGF-stimulated chemotaxis. On the other hand, HB-EGF is not a mitogen for cells expressing HER4, in contrast to its ability to stimulate both chemotaxis and proliferation in cells expressing HER1. It was concluded that HER4 is a newly described receptor for HB-EGF and that HB-EGF can activate two EGF receptor subtypes, HER1 and HER4, but with different biological responses.
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PMID:Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. 913 43

Studies on epidermal-growth-factor-like-, fibroblast- and transforming growth factors suggested their implication in tumorigenesis involving effects on tumour-cell proliferation and migration. In human transitional-cell carcinomas (TCC), enhanced expression of TGF alpha and EGF receptors correlated with an aggressive phenotype. However, little is known about functions of these growth factors in invasive TCCs. In this study, we performed protein- and RNA-expression studies on a set of growth factors and their receptors on the newly established invasive human TCC cell line designated 1207. The data were correlated with functional proliferation and migration studies. Similar expression patterns of many cellular markers, growth factors and their receptors were noted both in the original TCC tissue and in its derivative cell line, indicating the relevance of this cell line to the investigation of growth factor functions on TCC cells. The proliferation induction by EGF, TGF alpha, amphiregulin, heregulin alpha, FGF-1 and FGF-7 correlated with the presence of EGF receptors, c-erbB4 and FGFR2 (IIIb), respectively. Amphiregulin and heregulin alpha induced the most proliferation. In conformity with the low expression of TGF beta receptors I and II, TGF beta1, barely inhibited proliferation, while TGF alpha induced invasion of 1207 cells into Matrigel. These data support the notion that notably EGF-like proteins mediate TCC growth and invasion through autocrine pathways which can be reinforced by loss of TGF beta1 regulation.
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PMID:Expression and functions of EGF, FGF and TGFbeta-growth-factor family members and their receptors in invasive human transitional-cell-carcinoma cells. 913 55

Recent in vitro studies of the epidermal growth factor receptor (EGFR) family have revealed complex signaling interactions involving the production of ligand-mediated heterodimers synergistic for the transformation of cells in vitro. In a series of 70 patients with childhood medulloblastoma, we have used immunohistochemistry and Western blotting analysis to investigate the expression patterns of all four EGFR family members (EGFR, HER2, HER3, and HER4) and heregulin-alpha, a ligand for the HER3 and HER4 receptors. The majority of cases expressed two or more receptor proteins; coexpression of the HER2 and HER4 receptors occurred in 54%. Expression of the ligand heregulin-alpha was detected in 31% of tumors. To investigate whether coexpression results in receptor heterodimerization, we have also performed immunoprecipitation analysis of protein extracts from primary tumors, and we demonstrate various patterns of receptor interaction including between HER2 and HER4. In multivariate 25-year survival analysis with clinicopathological disease features, no individual receptor or heregulin-alpha achieved significance. In contrast, when considered together in the multivariate model, coexpression of HER2 and HER4 demonstrated independent prognostic significance (P = 0.006). These data suggest the hypothesis that HER2-HER4 receptor heterodimerization is of particular biological significance in this disease, and this report is the first to demonstrate potential clinical significance of EGFR family heterodimerization in human cancer. Finally, we have also analyzed expression of the AP-2 transcription factor implicated in the positive regulation of HER2 and HER3 gene transcription in malignant cells and reveal an association between AP-2 expression and not only HER2 and HER3, but also HER4 levels in medulloblastoma primary tumors.
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PMID:Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. 924 60

We observed no association between neoplastic epithelial immunostaining for either amphiregulin (AR) or heregulin (HRG) and presence of ER, EGFR/ERBB-2 overexpression, nodal status, or disease recurrence in 34 breast carcinomas. However, stromal cell staining for both correlated with outcome; 29% of stromal cell AR - cases recurred vs. 85% for AR + cases (p = 0.001), and 41% of stromal cell HRG - cases recurred vs. 82% of HRG + cases (p = 0.01). We conclude that both HRG and AR have significant biologic roles in breast carcinoma growth or progression via mediation of host-tumor interactions which favor aggressive tumor behavior.
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PMID:Clinicopathologic analysis of amphiregulin and heregulin immunostaining in breast neoplasia. 928 19


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