K-Ras mediates cytokine-induced formation of E-cadherin-based adherens junctions during liver development

被引:70
作者
Matsui, T
Kinoshita, T
Morikawa, Y
Tohya, K
Katsuki, M
Ito, Y
Kamiya, A
Miyajima, A
机构
[1] Univ Tokyo, Inst Mol & Cellular Biol, Bunkyo Ku, Tokyo 1130032, Japan
[2] Wakayama Med Sch, Dept Anat & Neurobiol, Wakayama 6408155, Japan
[3] Kansai Coll Oriental Med, Dept Anat, Kumatori, Osaka 5900433, Japan
[4] Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1188639, Japan
[5] Iwate Univ, Fac Agr, Morioka, Iwate 0208550, Japan
[6] Teikyo Univ, Biotechnol Res Ctr, KAST, Miyamae Ku, Kawasaki, Kanagawa 2160001, Japan
关键词
E-cadherin; homophilic adhesion; K-Ras; liver organogenesis;
D O I
10.1093/emboj/21.5.1021
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1021 / 1030
页数:10
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