Epidermal growth factor receptors: critical mediators of multiple receptor pathways

Hackel, Peter Oliver; Zwick, Esther; Prenzel, Norbert; Ullrich, Axel

doi:10.1016/s0955-0674(99)80024-6

Cited by 556 publications

(359 citation statements)

References 62 publications

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“…31,32 All of these pathways have been shown to be involved in the regulation of EGFR-mediated cell proliferation, protease secretion, and cell migration. 31 To identify the signal transduction pathways involved in the tumor-conditioned media-stimulated migratory response in the EGFR-BMSC, we added a series of specific signaling inhibitors in the assays of GL261-conditioned media-induced migration of EGFR-MSC (Fig 3). A MAP kinase kinase (MEK) inhibitor PD98059 and a p38 MAP kinase inhibitor SB202190 in the migration assays inhibited the migration of EGFR-MSC in a dosedependent manner (Fig 3a and b).…”

Section: Migration Of Egfr-msc Is Dependent On Pi3-k Mapk Protein Kmentioning

confidence: 99%

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

et al. 2005

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We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization. Unlike primary MSCs, EGFR-MSCs were resistant to FasL-mediated cytotoxicity and were capable of stimulating allogeneic mixed lymphocyte reaction, suggesting EGFR-MSCs possess suitable characteristics as vehicles for brain tumor immuno-gene therapy. Following injection at various sites, including the contralateral hemisphere in the brain of syngeneic mice, EGFR-MSCs were able to migrate toward GL261 gliomas or B16 melanoma in vivo. Finally, intratumoral injection with EGFR-MSC adenovirally engineered to secrete interferon-a to intracranial GL261 resulted in significantly prolonged survival in comparison to controls. These data indicate that EGFR-MSCs may serve as attractive vehicles for infiltrating brain malignancies such as malignant gliomas.

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Section: Migration Of Egfr-msc Is Dependent On Pi3-k Mapk Protein Kmentioning

confidence: 99%

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

et al. 2005

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“…In mammals, the EGFR family consists of four members, EGFR (or ErbB1), HER2 (or ErbB2/neu), HER3 (or ErbB3) and ErbB4 which are able to bind multiple peptide ligands (EGF, TGFa, amphiregulin, NDF, neuregulins, heregulins, HB-EGF, betacellulin and epiregulin) and, subsequently, to form homo-and heterodimeric complexes (Riese & Stern, 1998;Moghal & Sternberg, 1999;Hackel et al, 1999). Beside ligand-induced activation, EGFR can also be activated through ligandindependent mechanisms, for instance upon exposure of cells to ultraviolet radiations, oxidants, alkylating agents (Hackel et al, 1999) and oxidized lipids (Suc et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of the EGFR pathway is characterized by the following sequence of events: (i) stimulation of its intrinsic tyrosine kinase and phosphorylation of its own tyrosine residues (of its cytoplasmic domain) and of intracellular substrate proteins; (ii) binding on phosphotyrosine of SH2-and PTB-domain containing proteins, such as enzymes (src, phospholipase C-g1, phosphatidylinositol 3-kinase, SHP2 phosphotyrosine phosphatase, ras-GAP) or adaptor molecules (Shc isoforms, Grb2, Grb7, Nck, Cbl) which mediate downstream signalling (reviewed in Riese & Stern, 1998;Moghal & Sternberg, 1999;Hackel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Vacaresse

Vieira

Robbesyn

et al. 2001

British J Pharmacology

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1 Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported that the EGF receptor (EGFR) signalling pathway is activated by lipid peroxidation products (among them 4-hydroxynonenal, 4-HNE) contained in oxLDL. 2 The use of phenolic antioxidants, such as trolox, alpha-tocopherol, ca eic acid and tyrphostins A-25, A-46 or A-1478, showed that the oxLDL-induced EGFR activation is constituted by two separate components, the ®rst (early) one being antioxidant-insensitive, the second (late) being antioxidant-sensitive. 3 4-HNE derivatization of EGFR and EGFR activation induced by exogenous 4-HNE, suggest that the early (0.5 ± 3 h) component of oxLDL-induced EGFR activation is mediated (at least in part) by 4-HNE (and possibly by other oxidized lipids). This early component is antioxidantinsensitive. 4 The second component (4 ± 5 h) of the oxLDL-induced EGFR activation is antioxidant-sensitive, since it is blocked by antioxidants such as trolox, ca eic acid or PDTC, which act by blocking the cellular oxidative stress (H 2 O 2 generation) evoked by oxLDL. Conversely, exogenous H 2 O 2 induced EGFR autophosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This e ect is mediated in part through inhibition by oxidative stress of protein tyrosine phosphatases involved in EGFR dephosphorylation.

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“…Immediately following ligand binding, ErbB receptors from hetero and homo dimers thereby activating the intrinsic kinase activity of the receptor which leads to autophosphorylation of speci®c C terminal tyrosine residues. These phosphorylated residues couple to downstream src homology-2 (SH2) and phosphotyrosine binding (PTB) domain containing signaling molecules such as PLCg, Shc, cbl and PI3 kinase (Hackel et al, 1999). Activation of the grb2/sos, ras, raf, MEKK, MAP kinase pathway, which leads to cell proliferation, survival and cell motility, can occur directly through ErbB1 (Gale et al, 1993;Li et al,.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

et al. 2000

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Akt, when activated by IGF/insulin, can phosphorylate forkhead transcription factors. We undertook this study to determine whether epidermal growth factor (EGF) treatment could produce a signaling cascade resulting in phosphorylation of the forkhead transcription factor FKHR in a breast cancer cell line, MDA-MB-231. After establishing ErbB1, cbl, PI3 kinase and Akt were activated in EGF treated MDA-MB-231, we determined by immunoblot with FKHR antiserum that the electrophoretic mobility of FKHR was retarded after EGF treatment. This mobility retardation was reversible by treatment with alkaline phosphatase, and immunoblot with phospho-Ser 256 FKHR antibody further con®rmed phosphorylation on an Akt consensus site after EGF treatment. EGF stimulated FKHR phosphorylation was blocked by the PI3 kinase inhibitor LY294002, and the ErbB1 inhibitor AG1478. FKHR immunoblotting after puri®cation of nuclear and cytoplasmic proteins showed that EGF induced a simultaneous increase of FKHR in the cytoplasm and decrease in the nucleus. This ®nding was con®rmed by immuno¯uorescence staining. Treatment of cells with pharmacological inhibitors of PI3 kinase or ErbB1 blocked this e ect. Thus, these results demonstrate the phosphorylation and nuclear exclusion of FKHR after EGF treatment by a PI3 kinase dependent mechanism, and represent the ®rst report of growth factor regulation of endogenous FKHR localization Oncogene (2000) 19, 4574 ± 4581.

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Epidermal growth factor receptors: critical mediators of multiple receptor pathways

Cited by 556 publications

References 62 publications

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

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