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)

Glucosylceramide-based glycosphingolipids have been previously demonstrated to regulate negatively the formation of inositol 1,4,5-trisphosphate by phospholipase C-gamma1. In the present study, the depletion of endogenous glucosylceramide by D-t-EtDO-P4 in cultured ECV304 cells induced autophosphorylation of Src kinase at tyrosine residue 418 within the catalytic loop and dephosphorylation of Src kinase at tyrosine residues 529 within the carboxyl-terminal regulatory region. Phosphotransferase activities of Src kinase were also induced in the glucosylceramide-depleted cells. c-Src kinase activity and phosphorylations at Src Tyr-418 and epidermal growth factor (EGF) receptor Tyr-1068 were significantly enhanced by bradykinin in response to 100 nm D-t-EtDO-P4 compared with control cells. The phosphorylation and dephosphorylation on Tyr-418 and Tyr-529 residues of c-Src were reversed by treatment of 4-amino-5-(4-chlorophenyl)-7-t-butyl(pyrazolo)[3,4-d]pyrimidine (PP2), an inhibitor of Src kinase, in control cells. Glucosylceramide-depleted cells resisted treatment with PP2, and both phosphorylation of Tyr-418 and dephosphorylation of Tyr-529 induced by depletion of glucosylceramide were maintained. Compared with untreated cells, tyrosine phosphorylation of phospholipase C-gamma1 was enhanced by EGF stimulation in glucosylceramide-depleted cells, associated with enhanced tyrosine phosphorylation of the EGF receptor at Tyr-1068 and Tyr-1086 stimulated by EGF. The Src inhibitor, PP2, significantly blocked EGF-induced tyrosine phosphorylation of phospholipase C-gamma1 in control cells, whereas in glucosylceramide-depleted cells, suppression of Src kinase activity by PP2 toward EGF-induced tyrosine phosphorylation of phospholipase C-gamma1 was less significant. Thus the activation of Src kinase by depletion of glucosylceramide-based glycosphingolipids in cultured ECV304 cells is a critical up-stream event in the activation of phospholipase C-gamma1.
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PMID:Src kinase mediates the regulation of phospholipase C-gamma activity by glycosphingolipids. 1277 Nov 40

Taurine is present in high concentrations in neutrophils, and when the cells are stimulated taurine can react with hypochlorous acid (HOCl) to form taurine-chloramine (Tau-Cl). This compound retains oxidant activity and can affect the neutrophil itself or surrounding tissue cells. We have investigated the effects of Tau-Cl on MAPK signaling in human umbilical vein endothelial cells (HUVEC). Tau-Cl caused no loss in intracellular glutathione or inactivation of the thiol-sensitive enzyme glyceraldehyde-3-phosphate dehydrogenase, indicating that it had not entered the cells. However, stimulation of HUVEC with Tau-Cl (20-100 microM) induced the rapid activation of ERK within 10 min. This activation was abolished by inhibition of MEK by U0126, indicating that it was not because of direct oxidation of ERK. No activation of p38 was detected. These results suggest that Tau-Cl reacts with a cell membrane target that results in intracellular ERK activation. Tau-Cl over the same concentration range and time scale stimulated epidermal growth factor (EGF) receptor tyrosine phosphorylation in A431 cells and HUVEC. The EGF receptor inhibitor PD158780 significantly attenuated Tau-Cl-induced phosphorylation of both the EGF receptor and ERK. This implicates the EGF receptor in the upstream activation of ERK. The Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine had no effect on Tau-Cl-induced EGF receptor or ERK activation. We propose that Tau-Cl acts on an oxidant-sensitive target on the cell surface, this being either the EGF receptor itself or another target that can interact with the EGF receptor, with consequential activation of ERK.
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PMID:Extracellular oxidation by taurine chloramine activates ERK via the epidermal growth factor receptor. 1516 44

Mild doses of oxidative stress in the heart correlate with the induction of apoptosis or hypertrophy in cardiomyocytes (CMCs) and fibrosis or proliferation of fibroblasts. Three branches of mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinases (JNKs), extracellular signal-related kinases 1 and 2 (ERK1/2), and p38, are activated by oxidants in a variety of cell types, including CMCs. However, the initiation process of these signaling pathways remains unsolved. We explored the role of the epidermal growth factor (EGF) receptor in H(2)O(2)-induced MAPK activation using two different cell types from the same organ: CMCs and heart fibroblasts (HFs). Pretreatment of each cell type with EGF revealed differences in how CMCs and HFs responded to subsequent treatment with H(2)O(2): in CMCs, the second treatment resulted in little further activation of JNKs and ERK1/2, whereas HFs retained the full response of JNKs and ERK1/2 activation by H(2)O(2) regardless of EGF pretreatment. AG-1478 [4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline], a pharmacologic inhibitor of the EGF receptor tyrosine kinase, inhibited JNK and ERK1/2 activations but not p38 in both cell types. The data using the Src inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] resemble those found when using AG-1478 in either cell type. Pharmacologic inhibitors of matrix metalloproteinases (MMPs) further illustrated the difference between the two cell types. In HFs, MMP inhibitors GM6001 [N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide] and BB2516 [[2S-[N4(R(*)),2R(*),3S(*)]]-N4-[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methylpropyl)butanediamide, marimastat] inhibited JNKs and ERK1/2 activation without affecting p38 activation by H(2)O(2) inhibitors. In contrast, these MMP failed to significantly inhibit the activation of JNKs, ERKs, or p38 in CMCs. These data suggest the complexity of the cell type-dependent signaling web initiated by oxidants in the heart.
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PMID:Epidermal growth factor receptor-dependent and -independent pathways in hydrogen peroxide-induced mitogen-activated protein kinase activation in cardiomyocytes and heart fibroblasts. 1557 83

Within the kidney, angiotensin II type 2 (AT(2)) receptor mediates phospholipase A(2) (PLA(2)) activation, arachidonic acid release, epidermal growth factor (EGF) receptor transactivation, and mitogen-activated protein kinase activation. Arachidonic acid mimics this transactivation by an undetermined mechanism. The role of c-Src in mediating angiotensin II and arachidonic acid signaling was determined by employing immunocomplex kinase assay, Western blotting analysis, and protein immunoblotting on co-precipitated EGF receptor (EGFR) proteins and agarose conjugates of glutathione S-transferase fusion proteins containing the c-Src homology 2 (SH2) and SH3 domains. Angiotensin II induced extracellular signal-regulated kinase (ERK) activation in primary cultures of rabbit proximal tubule cells via the activation of c-Src and association of the EGFR with the c-Src SH2 domain, effects that were mimicked by arachidonic acid and its inactive analogue eicosatetraynoic acid. Inhibition of PLA(2) by mepacrine and methyl arachidonyl fluorophosphate, AT(2) receptor by PD123319, Src family kinases by, 1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d] pyrimidine (PP2) and c-Src by overexpression of a dominant-negative mutant of c-Src abrogated these effects. However, inhibitors of arachidonic acid metabolic pathways did not block these effects. The present work provides a new and novel paradigm for transactivation of a kinase receptor linked to a fatty acid, which may apply to activation of a variety of phospholipases and accompanying arachidonic acid release.
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PMID:Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor. 1659 96