Reconstitution of Mammary Gland Development In Vitro: Requirement of c-met and c-erbB2 Signaling for Branching and Alveolar Morphogenesis
Autor: | Eva Spitzer, Walter Birchmeier, Martin Sachs, Helga Naundorf, Catherin Niemann, Guido Hartmann, Volker Brinkmann |
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Rok vydání: | 1998 |
Předmět: |
C-Met
Receptor ErbB-2 Morpholines Morphogenesis Breast Neoplasms development of mammary gland Tropomyosin receptor kinase C neuregulin Receptor tyrosine kinase Wortmannin Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Mammary Glands Animal PI3 kinase Tumor Cells Cultured medicine Animals Humans Enzyme Inhibitors Glycoproteins Neuregulins Flavonoids biology Hepatocyte Growth Factor Cell Biology Proto-Oncogene Proteins c-met Molecular biology Cell biology Androstadienes Microscopy Electron MAPK kinase chemistry Chromones Calcium-Calmodulin-Dependent Protein Kinases biology.protein Hepatocyte growth factor Signal transduction Cell Adhesion Molecules Regular Articles Signal Transduction medicine.drug |
Zdroj: | The Journal of Cell Biology |
ISSN: | 1540-8140 0021-9525 |
Popis: | We have established a cell culture system that reproduces morphogenic processes in the developing mammary gland. EpH4 mouse mammary epithelial cells cultured in matrigel form branched tubules in the presence of hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the c-met tyrosine kinase receptor. In contrast, alveolar structures are formed in the presence of neuregulin, a ligand of c-erbB tyrosine kinase receptors. These distinct morphogenic responses can also be observed with selected human mammary carcinoma tissue in explant culture. HGF/SF-induced branching was abrogated by the PI3 kinase inhibitors wortmannin and LY294002. In contrast, neuregulin- induced alveolar morphogenesis was inhibited by the MAPK kinase inhibitor PD98059. The c-met–mediated response could also be evoked by transfection of a c-met specific substrate, Gab1, which can activate the PI3 kinase pathway. An activated hybrid receptor that contained the intracellular domain of c-erbB2 receptor suffices to induce alveolar morphogenesis, and was observed in the presence of tyrosine residues Y1028, Y1144, Y1201, and Y1226/27 in the substrate-binding domain of c-erbB2. Our data demonstrate that c-met and c-erbB2 signaling elicit distinct morphogenic programs in mammary epithelial cells: formation of branched tubules relies on a pathway involving PI3 kinase, whereas alveolar morphogenesis requires MAPK kinase. |
Databáze: | OpenAIRE |
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