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)

The mutant c-erbB-2 gene encoding a protein with Glu instead of Val-659 in the transmembrane domain is able to transform NIH3T3 cells, while the wild type c-erbB-2 unless overexpressed does not. The mutant c-erbB-2 protein shows enhanced tyrosine kinase activity in vitro. Transient expression of this active c-erbB-2 stimulated the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element, serum response element, and cyclic AMP response element. Particularly, stimulation of the TPA response element by active c-erbB-2 was prominent. In contrast, transient expression of wild type c-erbB-2 stimulated none of these elements. Transactivation of the TPA response element was also observed in a cell line that stably expresses active c-erbB-2. The active c-erbB-2-induced transactivation of the TPA response element was partially prevented either by down-regulation of protein kinase C or by the protein kinase C inhibitor H7. These results indicate that protein kinase C is partly involved in oncogenic signalling of the active c-erbB-2 protein that leads to Jun/Fos-mediated transcriptional activation in nuclei.
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PMID:Transactivation of the TPA-responsive element by the oncogenic C-erbB-2 protein is partly mediated by protein kinase C. 167 66

The effects of activating the Gq protein-coupled cholecystokinin (CCK) receptor on different proteins/signaling molecules in the mitogen-activated protein kinase (MAPK) cascade in pancreatic acinar cells were analyzed and compared with the effects of activating the tyrosine kinase-coupled epidermal growth factor (EGF) receptor. Both EGF and CCK octapeptide rapidly increased the activity of the MAPKs [extracellular signal-regulated kinase (ERK) 1 and ERK2], reaching a maximum within 2.5 min when 3.9- and 8.5-fold increases, respectively, were observed. The EGF-induced increase of MAPK activity was transient, with only a slight elevation after 30 min, whereas CCK-stimulated MAPK remained at a high level of activation to 60 min. The protein kinase C inhibitor GF-109203X abolished the activation by phorbol ester and inhibited the effect of CCK by 78% but had no effect on EGF-activated MAPK activity. EGF and CCK activated both forms of MAPK kinase (MEK), with CCK having a much larger effect, activating MEK1 by 6-fold and MEK2 by 10-fold, whereas EGF activated both MEKs by only 2-fold. Immunoblotting revealed three different forms of Raf in pancreatic acinar cells. Of the total basal Raf kinase activity, 3.7% was Raf-A, 89.0% was Raf-B, and 7.3% was c-Raf-1. All three forms of Raf were stimulated to a greater extent by CCK than by EGF, which was especially evident for Raf-A and c-Raf-1. The effect of CCK in activating Rafs was at least partially mimicked by stimulation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. EGF significantly increased GTP-bound Ras by 183 and 164% at 2.5 and 10 min, respectively; CCK and TPA had no measurable effect. Our study suggests that CCK and EGF activate the MAPK cascade by distinct mechanisms in pancreatic acinar cells.
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PMID:Cholecystokinin and EGF activate a MAPK cascade by different mechanisms in rat pancreatic acinar cells. 937 31

Cross-communication between different signaling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. In this paper we have explored the possibility that tumor necrosis factor (TNF) receptor signal cross-talks with epidermal growth factor (EGF) receptor signal on the nuclear factor-kappa B (NF-kappa B) activation pathway. We have demonstrated that overexpression of the EGF receptor (EGFR) in NIH3T3 cells significantly enhances TNF-induced NF-kappa B-dependent luciferase activity even without EGF, that EGF treatment has a synergistic effect on the induction of the reporter activity, and that this enhancement is suppressed by AG1478, EGFR-specific tyrosine kinase inhibitor. We also have shown that TNF induces tyrosine phosphorylation and internalization of the overexpressed EGFR in NIH3T3 cells and the endogenously expressed EGFR in A431 cells and that the transactivation by TNF is suppressed by N-acetyl-l-cysteine or overexpression of an endogenous reducing molecule, thioredoxin, but not by phosphatidylinositol 3-kinase inhibitors and protein kinase C inhibitor. Taken together, this evidence strongly suggests that EGFR transactivation by TNF, which is regulated in a redox-dependent manner, is playing a pivotal role in TNF-induced NF-kappa B activation.
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PMID:Redox-sensitive transactivation of epidermal growth factor receptor by tumor necrosis factor confers the NF-kappa B activation. 1133 89

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

Keratin intermediate filaments are heteropolymers composed of type I and type II keratins. Ultraviolet B (UVB) irradiation induces keratin expression by keratinocytes. Using SV40-transformed human keratinocytes (SVHK), we investigated the effect of UVB irradiation on keratin expression. UVB irradiation (10 mJ/cm(2)) increased keratin 5 and keratin 14 mRNAs and proteins without affecting cell viability. Upregulation of keratin 5 and keratin 14 was dependent on the dose of radiation: the effect was observed at 5 mJ/cm(2) and the maximal effect was observed at 10 mJ/cm(2). Higher UVB doses (more than 10 mJ/cm(2)) were cytotoxic. Expression of keratin 1 and keratin 10 was marginal in SVHK and was not affected at either the mRNA or protein level by UVB. The stimulatory effects on keratin 5 and keratin 14 expression were also observed in cultured normal human keratinocytes (NHK) and HaCaT keratinocytes. The tyrosine kinase inhibitor, genistein, and the epidermal growth factor (EGF) receptor inhibitor, AG1429, significantly suppressed the increase in expression of keratin 5 and keratin 14 by SVHK. In contrast, the suppressive effect was not observed with the protein kinase C inhibitor, H-7. Furthermore, pretreatment with neutralizing anti-EGF receptor antibody also suppressed UVB-induced keratin 5 and keratin 14 expression by SVHK, NHK and HaCaT cells. UVB irradiation did not affect the steady-state expression of TGF-alpha by SVHK. Immunoprecipitation and immunohistochemical studies revealed that UVB irradiation induced EGF receptor activation in the absence of EGF and TGF-alpha. These results indicate that UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK.
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PMID:Ultraviolet B irradiation increases keratin 5 and keratin 14 expression through epidermal growth factor receptor of SV40-transformed human keratinocytes. 1187 47