UNIPROT:P04626 - FACTA Search

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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated whether combined treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and trastuzumab could enhance the specific killing of cells that overexpress the erbB-2 receptor. The combination resulted in an enhancement of TRAIL-mediated apoptosis in all cell lines overexpressing erbB-2 receptor compared with either reagent alone. In contrast, there was no effect in cell lines with low levels of the erb-B2 receptor. Trastuzumab treatment resulted in down-regulation of the erbB-2 receptor in all erbB-2-overexpressing cell lines. Similar enhancement of TRAIL toxicity was observed when the erbB-2 receptor was down-regulated using antisense oligodeoxynucleotides. Down-regulation of the erbB-2 receptor protein by trastuzumab or antisense oligodeoxynucleotides decreased Akt kinase activation but not mitogen-activated protein kinase activation. Down-regulation of Akt kinase activity by a phosphatidylinositol 3'-kinase inhibitor (LY294002) also resulted in enhancement of TRAIL-mediated apoptosis. Expression of a constitutively active form of Akt kinase in an erbB-2-overexpressing cell line completely abrogated the increase in TRAIL-mediated apoptosis by trastuzumab and significantly reduced the biological effect of either reagent alone. Therefore, down-regulation of the erbB-2 receptor by trastuzumab enhances TRAIL-mediated apoptosis by inhibiting Akt kinase activity. These data suggest that the combination of trastuzumab and TRAIL may allow enhanced therapeutic efficacy and specificity in the treatment of erbB-2-overexpressing tumors.
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PMID:Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. 1140 68

Exposure to ambient particulate matter (PM) in the Utah Valley has previously been associated with a variety of adverse health effects. To investigate intracellular signaling mechanisms for pulmonary responses to Utah Valley PM inhalation, human primary airway epithelial cells were exposed to aqueous extracts of PM collected from the year before (Y1), during (Y2), and after (Y3) the closure of a local steel mill located in the Utah Valley in this study. Transfection with kinase-deficient extracellular signal-regulated kinase (ERK) 1 constructs partially blocked Utah Valley PM-induced interleukin (IL)-8 promoter reporter activity. The mitogen-activated protein kinase/ERK kinase (MEK) activity inhibitor PD-98059 significantly abolished IL-8 released in response to Utah Valley PM, as did the epidermal growth factor (EGF) receptor kinase inhibitor AG-1478. Western blotting showed that Utah Valley PM induced phosphorylation of EGF receptor tyrosine, MEK1/2, and ERK1/2, which could be ablated with AG-1478 or PD-98059. For all findings, the potency of Utah Valley PM collected during Y2 was found to be lower relative to that of Y1 and Y3. These data demonstrate that Utah Valley PM can induce IL-8 expression partially through the activation of the EGF receptor signaling.
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PMID:Activation of the EGF receptor signaling pathway in airway epithelial cells exposed to Utah Valley PM. 1143 24

ERalpha-negative breast tumors tend to overexpress growth factor receptors such as epidermal growth factor receptor or c-erbB-2. Raf-1 is a key intermediate in the signal transduction pathways of these receptors. High levels of constitutive Raf kinase (Deltaraf) activity imparts ERalpha- positive MCF-7 breast cancer cells with the ability to grow in the absence of estrogen. Deltaraf transfectants maintained in estrogen-depleted media showed greatly diminished responses to 17beta-estradiol or the pure antiestrogen ICI 182,780. Western blotting, ligand binding, and immunohistochemistry assays revealed a loss of ERalpha protein expression, and ribonuclease protection assays indicated that this correlated with loss of ERalpha message. In examining the basal expression of estrogen-induced genes in the stable transfectants or in transient cotransfection assays with an estrogen-response element- reporter construct and Deltaraf or constitutively active MAPK kinase (DeltaMEK), no ligand- independent activation of ERalpha was observed. Transient expression of Deltaraf and double-label immunostaining showed ERalpha was lost in those cells that transiently expressed Deltaraf. Abrogation of Raf signaling via treatment with the MEK inhibitors PD 098059 or U0126 resulted in reexpression of ERalpha. Similar studies performed with MCF-7 cells overexpressing epidermal growth factor receptor or c-erbB-2 confirmed that hyperactivation of MAPK resulted in down-regulation of ERalpha that was reversible by MEK inhibition or transfection with dominant negative ERK1 and ERK2 constructs. These data suggest that the hyperactivation of MAPK in epidermal growth factor receptor- or c-erbB-2-overexpressing breast cancer cells is directly responsible for generation of an ERalpha-negative phenotype and, more importantly, that this process may be abrogated by inhibiting these pathways, thus restoring ERalpha expression.
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PMID:Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells. 1146 58

Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal-regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-"tethered" ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of "insoluble" growth factor ligands and a novel mode of activation for growth factor receptors.
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PMID:Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. 1147 Aug 32

Desensitization and internalization of G-protein-coupled receptors can reflect receptor phosphorylation-dependent binding of beta-arrestin, which prevents G-protein activation and targets receptors for internalization via clathrin-coated vesicles. These can be pinched off by a dynamin collar, and proteins controlling receptor internalization can also mediate mitogen-activated protein kinase signaling. Gonadotropin-releasing hormone (GnRH) stimulates internalization of its receptors via clathrin-coated vesicles. Mammalian GnRH receptors (GnRH-Rs) are unique in that they lack C-terminal tails and do not rapidly desensitize, whereas non-mammalian GnRH-R have C-terminal tails and, where investigated, do rapidly desensitize and internalize. Using recombinant adenovirus expressing human and Xenopus GnRH-Rs we have explored the relationship between receptor internalization and mitogen-activated protein kinase signaling in HeLa cells with regulated tetracycline-controlled expression of wild-type or a dominant negative mutant (K44A) of dynamin. These receptors were phospholipase C-coupled and had appropriate ligand affinity and specificity. K44A dynamin expression did not alter human GnRH-R internalization but dramatically reduced internalization of Xenopus GnRH-R (and epidermal growth factor (EGF) receptor). Blockade of clathrin-mediated internalization (sucrose) abolished internalization of all three receptors. Both GnRH-Rs also mediated phosphorylation of ERK 2 and for both receptors, this was inhibited by K44A dynamin. The same was true for EGF- and protein kinase C-mediated ERK 2 phosphorylation. ERK 2 phosphorylation was also inhibited by a protein kinase C inhibitor but not affected by an EGF receptor tyrosine kinase inhibitor. We conclude that a) desensitizing and non-desensitizing GnRH-Rs are targeted for clathrin-coated vesicle-mediated internalization by functionally distinct mechanisms, b) GnRH-R signaling to ERK 2 is dynamin-dependent and c) this does not reflect a dependence on dynamin-dependent GnRH-R internalization.
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PMID:Differential internalization of mammalian and non-mammalian gonadotropin-releasing hormone receptors. Uncoupling of dynamin-dependent internalization from mitogen-activated protein kinase signaling. 1149 5

The interaction of the activated epidermal growth factor (EGF) receptor (EGFR) with the Src homology 2 (SH2) domain of Grb2 (growth-factor-receptor-bound protein 2) initiates signalling through Ras and mitogen-activated protein kinase. Grb2 can bind EGFR directly or through another SH2-containing protein, Shc. Activation of EGFRs by ligand also triggers rapid endocytosis of EGF-receptor complexes. To analyse the spatial and temporal regulation of EGFR interactions with SH2 domains in living cells, we have combined imaging microscopy with a modified method of measuring fluorescence resonance energy transfer (FRET) on a pixel-by-pixel basis using EGFR fused to cyan fluorescent protein (CFP) in pair with Grb2 or Shc fused to yellow fluorescent protein (YFP). Stimulation by EGF resulted in the recruitment of Grb2-YFP and YFP-Shc to cellular compartments that contained EGFR-CFP, and a large increase in the FRET signal. In particular, FRET measurements indicated that activated EGFR-CFP interacted with YFP-Shc and Grb2-YFP in membrane ruffles and endosomes. These results demonstrate that signalling via EGFRs can occur in the endosomal compartment. Moreover, in contrast with previous biochemical studies, FRET experiments show that a large pool of Grb2 and Shc is associated with EGFRs for a prolonged period after EGF stimulation.
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PMID:Internalization of the epidermal growth factor receptor: role in signalling. 1149 13

We examined the role of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase activation in G protein-coupled receptor (GPCR) agonist-induced mitogenesis in Swiss 3T3 and Rat-1 cells. Addition of EGFR tyrosine kinase inhibitors (e.g., tyrphostin AG-1478) abrogated bombesin-induced extracellular signal-regulated kinase (ERK) activation in Rat-1 cells but not in Swiss 3T3 cells, indicating the importance of cell context in determining the role of EGFR in ERK activation. In striking contrast, treatment with tyrphostin AG-1478 markedly (~70%) inhibited DNA synthesis induced by bombesin in both Swiss 3T3 and Rat-1 cells. Similar inhibition of bombesin-induced DNA synthesis in Swiss 3T3 cells was obtained using four structurally different inhibitors of EGFR tyrosine kinase. Furthermore, kinetic analysis indicates that EGFR function is necessary for bombesin-induced mitogenesis in mid-late G(1) in both Swiss 3T3 and Rat-1 cells. Our results indicate that EGFR kinase activity is necessary in mid-late G(1) for promoting the accumulation of cyclins D1 and E and implicate EGFR function in the coupling of GPCR signaling to the activation of the cell cycle.
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PMID:EGF receptor function is required in late G(1) for cell cycle progression induced by bombesin and bradykinin. 1150 66

The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.048) and in relapsed tumors (P = 0.021). The expression of epidermal growth factor (EGF) receptor (P = 0.037), transforming growth factor alpha (TGF-alpha; P < 0.001), and HER2 (P = 0.066; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation. In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0.002). In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor antibody ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation. In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients. Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression. The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies.
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PMID:Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. 1152 47

Amplification and/or mutations of the epidermal growth factor (EGF) receptor have been frequently reported in human malignant gliomas, the most common primary tumor of the adult central nervous system. We have analyzed a panel of established human glioma cell lines for EGF receptor expression. The EGF receptor was expressed in all of the glioma cell lines tested, with highest levels found in the cell line U343MG-a. In addition, various amounts of a truncated form of the EGF receptor were detected. The platelet-derived growth factor (PDGF) alpha receptor, analyzed for comparison, was expressed at low levels in human glioma cells, with the exception of U-118MG and U-373MG cells. The truncated form of the EGF receptor has been discussed as a constitutively active variant of the receptor. Using antibodies directed against the active form of the EGF receptor, we show here that the truncated variant of the EGF receptor in U343MG-a cells is not in the active conformation. However, the full-length EGF receptor, highly expressed in U343MG-a cells, was very rapidly activated following EGF treatment. In line with this, phosphorylation and activation of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) in U343MG-a cells required administration of EGF. Moreover, using highly specific riboprobes we observed that EGF signaling increased the Egr-1 mRNA concentration in human glioma cells within 30 min. The increase in the Egr-1 mRNA concentration was followed by a transient synthesis of the Egr-1 protein. Likewise, Egr-1 mRNA and protein concentrations were increased in U-118MG and U-373MG cells treated with PDGF. The synthesis of Egr-1 in human glioma cells as a result of EGF or PDGF stimulation indicates that Egr-1 may be an important "late" part of the EGF and PDGF-initiated signaling cascades suggesting that Egr-1 functions as a "third messenger" in glioma cells connecting growth factor stimulation with changes in gene transcription.
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PMID:Epidermal growth factor and platelet-derived growth factor induce expression of Egr-1, a zinc finger transcription factor, in human malignant glioma cells. 1153 37

In a recent study, inhibition of cellular ganglioside synthesis blocked growth factor-induced fibroblast proliferation. Conversely, enrichment of cell membrane gangliosides by ganglioside preincubation enhanced growth factor-elicited cell proliferation. In the absence of serum and growth factors, NeuNAcalpha2-3Galbeta1-3GalNAcbeta1-4(NeuNAcalpha2-3)Galbeta1-4Glcbeta1-1Cer (G(D1a)) acted like a growth factor when cells were pretreated with the ganglioside, stimulating proliferation of normal human dermal fibroblasts and Swiss 3T3 fibroblasts. In contrast, growth inhibition was observed when high concentrations of gangliosides were continuously present in the culture medium during incubation of fibroblasts with growth factors (Li, R., Manela, J., Kong, Y., and Ladisch, S. (2000) J. Biol. Chem. 275, 34213-34223). Here, we investigated the mechanisms whereby gangliosides elicit proliferation-coupled signaling in normal human dermal fibroblasts. Incubation of the fibroblasts with G(D1a) enhanced epidermal growth factor (EGF) receptor autophosphorylation and Ras and MAPK activation in a dose-dependent manner. Exposure of the cells to G(D1a) also enhanced the phosphorylation of Elk-1 by the activated MAPK. Brief pretreatment of the cells with PD98059 blocked the enhancing effect of gangliosides on EGF-induced MAPK activation. In the absence of serum and growth factors, G(D1a) incubation induced phosphorylation of Src kinase, Ras activation, and phosphorylation of MAPK and Elk-1 in a dose-dependent manner. The activation of Src kinase was confirmed by enhanced Src kinase activity. Brief treatment of the cells with PP1 blocked the activation of Src kinase and MAPK. Again, PD98059 treatment inhibited ganglioside-elicited MAPK phosphorylation. Among the gangliosides tested, G(D1a), was the most active molecule, whereas lactosylceramide was the least active one, indicating relative structural specificity of the ganglioside action. In conclusion, gangliosides promote fibroblast proliferation through enhancement of growth factor signaling and activation of Src kinase.
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PMID:Enhancement of epidermal growth factor signaling and activation of SRC kinase by gangliosides. 1153 85

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