期刊
EMBO JOURNAL
卷 21, 期 5, 页码 1021-1030出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/21.5.1021
关键词
E-cadherin; homophilic adhesion; K-Ras; liver organogenesis
The E-cadherin-based adherens junction (AJ) is essential for organogenesis of epithelial tissues including the liver, although the regulatory mechanism of AJ formation during development remains unknown. Using a primary culture system of fetal hepatocytes in which oncostatin M (OSM) induces differentiation, we show here that OSM induces AJ formation by altering the subcellular localization of AJ components including E-cadherin and catenins. By retroviral expression of dominant-negative forms of signaling molecules, Ras was shown to be required for the OSM-induced AJ formation. Fetal hepatocytes derived from K-Ras knockout (K-Ras(-/-)) mice failed to form AJs in response to OSM, whereas AJ formation was induced normally by OSM in mutant hepatocytes lacking both H-Ras and N-Ras. Moreover, the defective phenotype of K-Ras(-/-) hepatocytes was restored by expression of K-Ras, but not by H-Ras and N-Ras. Finally, pull-down assays using the Ras-binding domain of Raf1 demonstrated that OSM directly activates K-Ras in fetal hepatocytes. These results indicate that K-Ras specifically mediates cytokine signaling for formation of AJs during liver development.
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