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

A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as 'ectodomain shedding', under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
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PMID:Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase. 1122 64

Substance P is a member of the tachykinin family of neuropeptides that plays an important role in pain transmission, neurogenic inflammatory diseases and the adaptive response to stress. Substance P exerts its biological activities via binding to a G-protein coupled receptor of the neurokinin (NK) receptor family. Here, we show by Western blot experiments that substance P induced a transient synthesis of the zinc finger transcriptional regulator Egr-1 in human glioma cells. Substance P-induced stimulation of Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that transactivation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase (ERK) are essential for substance P/NK-1 receptor-induced activation of Egr-1 biosynthesis. Moreover, we show that the signaling cascade initiated by substance P or EGF are indistinguishable, including the activation of the EGF receptor, the activation of ERK, and the final stimulation of Egr-1 biosynthesis. The synthesis of Egr-1 in glioma cells as a result of substance P stimulation suggests that substance P exerts long-term effects in glioma cells via Egr-1-mediated gene transcription.
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PMID:Substance P induced biosynthesis of the zinc finger transcription factor Egr-1 in human glioma cells requires activation of the epidermal growth factor receptor and of extracellular signal-regulated protein kinase. 1238 23

The G-protein coupled receptor (GPCR) fMLP receptor (FPR) and the two receptors tyrosine kinase (RTK), the nerve growth factor (NGF) receptor TrkA and the epidermal growth factor (EGF) receptor (EGFR) are involved in reactive oxygen species (ROS), matrix metalloproteinase-9 (MMP-9) production and CD11b membrane integrin upregulation. We show that in monocytes the three receptors crosstalk each other to modulate these pro-inflammatory mediators. Tyrphostin AG1478, the EGFR inhibitor, inhibits fMLP and NGF-associated ROS production, fMLP-associated CD11b upregulation and NGF-induced TrkA phosphorylation; K252a, the NGF receptor inhibitor, inhibits fMLP or EGF-associated ROS production, CD11b expression and EGF-induced EGFR phosphorylation; cyclosporine H, the FPR inhibitor inhibits EGF or NGF-associated ROS production, EGF-associated CD11b upregulation and prevents EGFR and TrkA phosphorylation by their respective ligand EGF and NGF. In response to fMLP, TrkA phosphorylation is inhibited by the EGFR inhibitor while EGFR phosphorylation is inhibited by the TrkA inhibitor. Receptor crosstalks are Src and ERK dependent. Down-regulation of each receptor by specific siRNA suppresses the ability of the two other receptors to promote ligand-mediated ERK phosphorylation and pro-inflammatory activities including ROS, MMP-9 production and CD11b upregulation. Thus, in monocytes GPCR ligands' activity involves activation of RTK while RTK-ligands activity engages GPCR-signalling molecules.
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PMID:Crosstalks between the receptors tyrosine kinase EGFR and TrkA and the GPCR, FPR, in human monocytes are essential for receptors-mediated cell activation. 2056 83

Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-Fos, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-Fos, clozapine elevated expression 24h after administration, a timeframe consistent with ERK activation at 8h. Alternatively, haloperidol stimulation of c-Fos levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia.
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PMID:Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum. 2314 70