Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transactivation of the epidermal growth factor (EGF) receptor (EGFR) has been proposed to represent an essential link between G-protein-coupled receptors and the mitogen-activated protein kinase (MAPK) pathway in various cell types. In the present work we report, in contrast, that in A431 cells bradykinin transinactivates the EGFR and stimulates MAPK activity independently of EGFR tyrosine phosphorylation. Both effects of bradykinin are mediated by a pertussis-toxin-insensitive G-protein. Three lines of evidence suggest the activation of a protein tyrosine phosphatase (PTP) by bradykinin: (i) treatment of A431 cells with bradykinin decreases both basal and EGF-induced EGFR tyrosine phosphorylation, (ii) this effect of bradykinin can be blocked by two different PTP inhibitors, and (iii) bradykinin significantly increased the PTP activity in total A431 cell lysates when measured in vitro. The transmembrane receptor PTP sigma was identified as a putative mediator of bradykinin-induced downregulation of EGFR autophosphorylation. Activation of MAPK in response to bradykinin was insensitive towards AG 1478, a specific inhibitor of EGFR tyrosine kinase, but was blocked by wortmannin or bisindolylmaleimide, inhibitors of phosphatidylinositol 3-kinase (PI3-K) and protein kinase C (PKC) respectively. These results also suggest that the bradykinin-induced activation of MAPK is independent of EGFR and indicate a pathway involving PI3-K and PKC. In addition, bradykinin evokes a rapid and transient increase in Src kinase activity. Although Src does not participate in bradykinin-induced stimulation of PTP activity, inhibition of Src by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine leads to an increase in MAPK activation by bradykinin. Our results suggest that in A431 cells the G(q/11)-protein-coupled bradykinin B(2) receptor may stimulate PTP activity and thereby transinactivate the EGFR, and may simultaneously activate MAPK by an alternative signalling pathway which can bypass EGFR.
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PMID:Protein-tyrosine-phosphatase-mediated epidermal growth factor (EGF) receptor transinactivation and EGF receptor-independent stimulation of mitogen-activated protein kinase by bradykinin in A431 cells. 1074 73

Many receptors coupled to the pertussis toxin-sensitive G(i/o) proteins stimulate the mitogen-activated protein kinase (MAPK) pathway. The role of the alpha chains of these G proteins in MAPK activation is poorly understood. We investigated the ability of Galpha(o) to regulate MAPK activity by transient expression of the activated mutant Galpha(o)-Q205L in Chinese hamster ovary cells. Galpha(o)-Q205L was not sufficient to activate MAPK but greatly enhanced the response to the epidermal growth factor (EGF) receptor. This effect was not associated with changes in the state of tyrosine phosphorylation of the EGF receptor. Galpha(o)-Q205L also potentiated MAPK stimulation by activated Ras. In Chinese hamster ovary cells, EGF receptors activate B-Raf but not Raf-1 or A-Raf. We found that expression of activated Galpha(o) stimulated B-Raf activity independently of the activation of the EGF receptor or Ras. Inactivation of protein kinase C and inhibition of phosphatidylinositol-3 kinase abolished both B-Raf activation and EGF receptor-dependent MAPK stimulation by Galpha(o). Moreover, Galpha(o)-Q205L failed to affect MAPK activation by fibroblast growth factor receptors, which stimulate Raf-1 and A-Raf but not B-Raf activity. These results suggest that Galpha(o) can regulate the MAPK pathway by activating B-Raf through a mechanism that requires a concomitant signal from tyrosine kinase receptors or Ras to efficiently stimulate MAPK activity. Further experiments showed that receptor-mediated activation of Galpha(o) caused a B-Raf response similar to that observed after expression of the mutant subunit. The finding that Galpha(o) induces Ras-independent and protein kinase C- and phosphatidylinositol-3 kinase-dependent activation of B-Raf and conditionally stimulates MAPK activity provides direct evidence for intracellular signals connecting this G protein subunit to the MAPK pathway.
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PMID:Activation of B-Raf and regulation of the mitogen-activated protein kinase pathway by the G(o) alpha chain. 1074 19

TRH has been found to stimulate tyrosine phosphorylation of the epidermal growth factor (EGF) receptor. A specific EGF receptor kinase inhibitor, tyrphostin AG1478, substantially reduced TRH-stimulated tyrosine phosphorylation of the EGF receptor. TRH-induced EGF receptor phosphorylation was found to lead to the recruitment of the adapter proteins Grb2 and Shc. TRH treatment also led to phosphorylation of the related receptor tyrosine kinase, HER2. HER2 activation likely contributes to downstream signaling events and enhances EGF receptor action. TRH-induced tyrosine phosphorylation of the EGF receptor was reduced by incubation with a protein kinase C (PKC) kinase inhibitor, GF109203X. EGF receptor phosphorylation was required for full TRH-induced activation of mitogen-activated protein kinase (MAPK) and stimulation of specific transcriptional responses.
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PMID:Thyrotropin-releasing hormone stimulates phosphorylation of the epidermal growth factor receptor in GH3 pituitary cells. 1097 12

The mechanisms by which Gi and Gq protein- coupled receptors mediate mitogenic signaling in osteoblast-like cells are unknown and were investigated in MC3T3-E1 cells using specific receptor agonists such as lysophosphatidic acid (LPA) and prostaglandin F2alpha (PGF2alpha). In contrast to their implication in epidermal growth factor (EGF) receptor tyrosine kinase signaling, the adaptor protein Shc, the Grb2/Sos complex, and the small G protein Ras were not involved in the activation of Erk induced by either LPA or PGF2alpha in MC3T3-E1 cells, suggesting that activation of Erk by Gi and Gq protein-coupled receptors is Ras independent in these cells. Using specific kinase inhibitors and kinetic analyses, we provide evidence for two distinct components in the activation of Erk by Gi and Gq protein-coupled receptors in MC3T3-E1 cells including an Src-like kinase-dependent pathway and a protein kinase C (PKC)-dependent mechanism. Functional analyses suggested that these two components are required for optimal DNA synthesis in response to LPA and PGF2alpha. These results suggest the implication of two pathways in the stimulation of Erk and cell replication by growth factors acting through Gi and Gq protein-coupled receptors in bone-forming cells.
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PMID:Evidence for the involvement of two pathways in activation of extracellular signal-regulated kinase (Erk) and cell proliferation by Gi and Gq protein-coupled receptors in osteoblast-like cells. 1097 90

We investigated a signaling pathway leading to activation of extracellular signal-regulated protein kinase (Erk) 1 and 2 in Rat-2 cells stimulated with sphingosine 1-phosphate (S1P). S1P treatment transiently activated Erk-1/-2 in a dose-dependent manner, and its activation was blocked by pertussis toxin, expression of RasN17, or inhibition of Raf or MEK-1/-2. S1P-induced activation of Erk-1/-2 was also suppressed by the inhibition of epidermal growth factor (EGF) receptor tyrosine kinase with the specific inhibitor AG1478, suggesting that activation of EGF receptor tyrosine kinase was involved in the signaling pathway. S1P-induced Erk-1/-2 activation was enhanced up to 2-fold by inhibiting protein kinase C (PKC) with GF109203X, and PKC inhibition in the absence of S1P treatment also activated Erk-1/-2. The stimulatory effects of Erk-1/-2 activation by PKC inhibition was blocked by treating cells with AG1478, suggesting the involvement of PKC in the regulation of EGF receptor tyrosine kinase activation that leads to Erk-1/-2 activation. Together, these results suggest that S1P activates the EGF receptor through a PKC-dependent pathway that links Ras signaling to the activation of Erk-1/-2 in Rat-2 cells.
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PMID:Sphingosine 1-phosphate activates Erk-1/-2 by transactivating epidermal growth factor receptor in rat-2 cells. 1118 56

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMC) and has been implicated its pathogenic role in vascular remodelling. However, the signalling pathways by which thrombin mediates its mitogenic response are not fully understood. We have previously reported that thrombin activates p38 mitogen-activated protein kinase (p38 MAPK) by a tyrosine kinase-dependent mechanism, and that p38 MAPK has a role in thrombin-induced mitogenic response in rat VSMC. In the present study, we examine the involvement of epidermal growth factor (EGF) receptor in thrombin-induced p38 MAPK activation. We found that thrombin induced EGF receptor tyrosine phosphorylation (transactivation) in A10 cells, a clonal VSMC cell line. A selective inhibitor of EGF receptor kinase (AG1478) inhibited the p38 MAPK activation in a dose-dependent manner, whereas it had no effect on the response to platelet-derived growth factor (PDGF). EGF receptor phosphorylation induced by thrombin was inhibited by BAPTA-AM and GF109203X, which suggest a requirement for intracellular Ca(2+) increase and protein kinase C. We next examined the effect of AG1478 on thrombin-induced DNA synthesis. AG1478 inhibited thrombin-induced DNA synthesis in a dose-dependent manner. In contrast, PDGF-induced DNA synthesis was not affected by AG1478. In conclusion, these data suggest that the EGF receptor transactivation and subsequent p38 MAPK activation is required for thrombin-induced proliferation of VSMC.
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PMID:Thrombin-induced p38 mitogen-activated protein kinase activation is mediated by epidermal growth factor receptor transactivation pathway. 1130 36

This study examined the premise that the atherogenic lipoprotein, beta-migrating very low density lipoprotein (betaVLDL), might activate the mitogen-activated protein (MAP) kinases ERK1/ERK2, thereby contributing to the induction of smooth muscle cell proliferation in atherosclerosis. The data show that betaVLDL activates rabbit smooth muscle cell ERK1/ERK2. Interestingly, ERK1/ERK2 activation is mediated by G protein-coupled receptors that transactivate the epidermal growth factor (EGF) receptor. betaVLDL-induced MAP kinase activation depends on Ras and Src activity as well as protein kinase C. The inhibition of lysosomal degradation of betaVLDL has no effect on ERK1/ERK2 activation. The contribution of betaVLDL-induced activation of ERK1/ERK2 to smooth muscle cell proliferation was also explored. betaVLDL induces expression of egr-1 and c-fos mRNA. Despite its ability to stimulate early gene expression, betaVLDL alone is unable to inspire quiescent cells into S phase. When added in conjunction with EGF, however, stimulation of [(3)H]thymidine incorporation into DNA and an increase in histone gene expression are observed. Moreover, betaVLDL plus EGF synergistically induce cyclin D1 expression and down-regulate p27(KIP1) expression. The addition of either betaVLDL or EGF stimulates a robust activation of ERK1/ERK2, but the addition of both agents simultaneously sustains the activation for a longer time period. Inhibition of MAP kinase kinase, pertussis toxin-sensitive G proteins, the EGF receptor, or protein kinase C blocks betaVLDL plus EGF-induced proliferation, demonstrating that activation of the betaVLDL-induced signaling pathway results in smooth muscle cell proliferation.
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PMID:beta-Migrating very low density lipoprotein (beta VLDL) activates smooth muscle cell mitogen-activated protein (MAP) kinase via G protein-coupled receptor-mediated transactivation of the epidermal growth factor (EGF) receptor: effect of MAP kinase activation on beta VLDL plus EGF-induced cell proliferation. 1137 98

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

We investigated the possibility that opioids activate a tyrosine kinase (TK) that mediates cardioprotection in an in vivo rat model of myocardial infarction. All animals underwent 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk (IS/AAR). Control animals had an IS/AAR of 58.2 +/- 0.6. Cardioprotection was induced with the delta1- or delta1/delta2-selective opioid agonists, TAN-67, or D-Ala D-Leu enkephalin (DADLE). Both significantly reduced IS/AAR (28.8 +/- 3.6 and 34.8 +/- 3.8, respectively). The general TK inhibitor, genistein, abolished cardioprotection produced by TAN-67 or DADLE (59.1 +/- 3.2 and 61.5 +/- 3.4, respectively), whereas the structural analog, daidzein, lacking TK inhibitory activity, did not. Interestingly, the selective Src/epidermal growth factor (EGF) receptor TK inhibitor, lavendustin A, did not abolish TAN-67-induced cardioprotection (22.1 +/- 6.8). Similarly, the Src-selective TK antagonist, PP2, had no effect on DADLE-induced cardioprotection (31.1 +/- 7.3). These unexpected findings suggest that Src and EGF receptor TKs are not important in the genesis of cardioprotection produced by TAN-67. Finally, we demonstrate that genistein did not affect protein kinase C (PKC) translocation induced by TAN-67. These data suggest that a TK, but most likely not an Src/EGF receptor TK, is important in cardioprotection via opioid receptor stimulation and that the pathway for TK activation is downstream from or parallel to PKC activation in the in situ rat heart since genistein could not affect PKC translocation of selective isoforms induced by TAN-67 and assessed by immunohistochemistry.
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PMID:Dependence of delta1-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway. 1160 57

G-protein-coupled receptors (GPCRs) induce the phosphorylation of mitogen-activated protein (MAP) kinase by actions on any of a number of signal transduction systems. Previous studies have revealed that activation of the G(q)-coupled metabotropic glutamate receptor 5 (mGluR5) induces phosphorylation of the MAP kinase extracellular signal-regulated kinase 2 (ERK2) in cultured rat cortical astrocytes. We performed a series of studies to determine the mechanisms underlying mGluR5-induced phosphorylation of MAP kinase in these cells. Interestingly, our studies suggest that mGluR5-mediated ERK2 phosphorylation is dependent on the activation of G(alphaq) but is not mediated by the activation of phospholipase Cbeta1, activation of protein kinase C, or increases in intracellular calcium. Studies with peptide inhibitors suggest that this response is not dependent on G(betagamma) subunits. However, the activation of ERK2 was dependent on activation of the epidermal growth factor (EGF) receptor and activation of a Src family tyrosine kinase. Furthermore, activation of mGluR5 induced an association of this receptor and the EGF receptor, suggesting the formation of a signaling complex involved in the activation of ERK2. These data suggest that mGluR5 increases ERK2 phosphorylation in astrocytes by a novel mechanism involving the activation of G(alphaq) and both receptor and nonreceptor tyrosine kinases but that is independent of the activation of phospholipase Cbeta1.
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PMID:Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor. 1173 72


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