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

Scatter factor (SF), which dissociates epithelial cell colonies into individual cells and stimulates the migration of epithelial cells, is identical to hepatocyte growth factor (HGF), a mitogen for melanocytes, endothelial cells and epithelial cells, including hepatocytes. It was previously shown by cDNA transfection that the mitogenic effect of SF/HGF is mediated by activation of the tyrosine phosphorylation of the c-Met receptor (the c-met proto-oncogene product). In this study, we constructed a cDNA encoding a chimeric receptor composed of the extracellular domain of the epidermal growth factor (EGF) receptor and the transmembrane and cytoplasmic domains of the c-Met receptor. We transfected the cDNA into the B16-F1 mouse melanoma cell line to investigate whether the cell dissociation and motility were mediated through this chimeric receptor following ligand stimulation. The chimeric receptor cDNA was expressed in the transfected cells and the protein product was transported to the cell surface in the correct transmembrane orientation. EGF treatment of the chimeric receptor-expressing cells markedly enhanced tyrosine phosphorylation of the chimeric receptor and led to scattered morphology and enhanced motility. This scattered morphology was inhibited by a tyrosine kinase inhibitor. Based on these results, we concluded that the cell dissociation and motility triggered by SF/HGF were mediated through the cytoplasmic domain of the c-Met receptor by activation of its tyrosine kinase. Thus, it is likely that the different biological effects of SF/HGF are mediated by different intracellular signal cascades.
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PMID:The cell dissociation and motility triggered by scatter factor/hepatocyte growth factor are mediated through the cytoplasmic domain of the c-Met receptor. 768 22

Pulmonary epithelial cells are important in lung growth, development, and injury. H441 pulmonary adenocarcinoma cells may be a useful model for studying pulmonary epithelial cell growth factor responses in vitro. Isolated pulmonary epithelial type II cells proliferate in response to transforming growth factor (TGF)-alpha via the epidermal growth factor (EGF) receptor. Type II cells also proliferate in response to hepatocyte growth factor (HGF). In the present study, H441 cell responses to these growth factors were examined, and compared to type II cells. Both the EGF-R and the c-met proto-oncogene receptor, to which HGF binds, were immunoprecipitated from H441 cells. In H441 cells, addition of TGF-alpha resulted in phosphorylation of the EGF receptor and increased cell number and tritiated thymidine incorporation. Incubation with HGF resulted in phosphorylation of its c-met proto-oncogene receptor in type II and H441 cells, and also increased cell number and tritiated thymidine incorporation. Both HGF and TGF-alpha stimulated phosphorylation of the intracellular signaling molecules p42 and p44 mitogen activated protein kinases in H441 cells. H441 cells exhibited responses to mitogenic growth factors similar to type II cells and may be useful as a model for type II cell growth factor responses and signal transduction.
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PMID:H441 pulmonary epithelial cell mitogenic effects and signaling pathways in response to HGF and TGF-alpha. 945 67

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

The development of personalized medicine with a focus on novel targeted therapies has supplanted the one-size-fits-all approach to the treatment of many cancers, including non-small cell lung cancer. Targeted therapies, if given to a patient subpopulation enriched by the presence of relevant molecular targets, can often abrogate cell signaling that perpetuates cancer progression. Critical targets activating procancer pathways include, but are not limited to, epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), vascular endothelial growth factor (VEGF), VEGF receptor, GTPase KRAS (KRAS), receptor tyrosine protein kinase erbB-2 (HER2), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), serine/threonine-protein kinase B-raf (BRAF), and insulin-like growth factor 1 receptor (IGF-1R). Some target-directed therapies, such as epidermal growth factor receptor tyrosine kinase inhibitors and anti-VEGF monoclonal antibody, have already been approved for clinical use. Others, such as those targeted to MET, VEGFR, HER2, PIK3CA, and IGF-1R, are in clinical testing. This review describes molecular targets in non-small cell lung cancer that are in development or being clinically applied and their implications for developing novel anticancer therapies for this previously refractory malignancy.
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PMID:Novel therapeutic targets in non-small cell lung cancer. 2184 57