Article abstract
Nature Cell Biology 10, 513 - 526 (2008)
Published online: 20 April 2008 | doi:10.1038/ncb1714
Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1
Shigetomo Fukuhara1, Keisuke Sako1, Takashi Minami2, Kazuomi Noda1, Hak Zoo Kim3, Tatsuhiko Kodama2, Masabumi Shibuya4, Nobuyuki Takakura5, Gou Young Koh3 & Naoki Mochizuki1
Abstract
Tie2 belongs to the receptor tyrosine kinase family and functions as a receptor for Angiopoietin-1 (Ang1). Gene-targeting analyses of either Ang1 or Tie2 in mice reveal a critical role of Ang1–Tie2 signalling in developmental vascular formation. It remains elusive how the Tie2 signalling pathway plays distinct roles in both vascular quiescence and angiogenesis. We demonstrate here that Ang1 bridges Tie2 at cell–cell contacts, resulting in trans-association of Tie2 in the presence of cell–cell contacts. In clear contrast, in isolated cells, extracellular matrix-bound Ang1 locates Tie2 at cell–substratum contacts. Furthermore, Tie2 activated at cell–cell or cell–substratum contacts leads to preferential activation of Akt and Erk, respectively. Microarray analyses and real-time PCR validation clearly show the differential gene expression profile in vascular endothelial cells upon Ang1 stimulation in the presence or absence of cell–cell contacts, implying downstream signalling is dependent upon the spatial localization of Tie2.
- Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
- The Research Center for Advanced Science and Technology, University of Tokyo, Laboratory for System Biology and Medicine, 4-6-1, Komaba, Meguro, Tokyo, 153-8904, Japan.
- Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Guseong-dong, Daejeon, 305-701, Korea.
- Division of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
- Department of Signal Transduction, Research Institute of Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka, 565-0871, Japan.
Correspondence to: Shigetomo Fukuhara1 e-mail: fuku@ri.ncvc.go.jp
Correspondence to: Naoki Mochizuki1 e-mail: nmochizu@ri.ncvc.go.jp
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