K-Ras mediates cytokine-induced formation of E-cadherin-based adherens junctions during liver development.
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.
Matsui
Takaaki
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Kinoshita
Taisei
T
Morikawa
Yoshihiro
Y
Tohya
Kazuo
K
Katsuki
Motoya
M
Ito
Yoshiaki
Y
Kamiya
Akihide
A
Miyajima
Atsushi
A
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005326:Fetal Proteins / Q000502:physiology*; D011905:Genes, ras; D005816:Genetic Complementation Test; D022781:Hepatocytes / Q000187:drug effects / Q000648:ultrastructure*; D008099:Liver / Q000196:embryology*; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D010750:Phosphoproteins / Q000032:analysis; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D005326:Fetal Proteins; D008565:Membrane Proteins; C508352:Osm protein, mouse; D010455:Peptides; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C569043:Tjp1 protein, mouse; D015534:Trans-Activators; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D053683:Oncostatin M; D003907:Dexamethasone; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras)