Phosphatidylinositol 3-kinase class II α-isoform PI3K-C2α is required for transforming growth factor β-induced smad signaling in endothelial cells

フォーマット:

論文

責任表示:

Aki, Sho ; Yoshioka, Kazuaki ; Okamoto, Yasuo ; Takuwa, Noriko ; Takuwa, Yoh

言語:

英語

出版情報:

American Society for Biochemistry and Molecular Biology, 2015-03-06

著者名:

• Aki, Sho
• Yoshioka, Kazuaki
• Okamoto, Yasuo
• Takuwa, Noriko
• Takuwa, Yoh

掲載情報:

Journal of Biological Chemistry

ISSN:

0021-9258      

巻:

290

通号:

10

開始ページ:

6086

終了ページ:

6105

バージョン:

author

概要:

We have recently demonstrated that the PI3K class II-α isoform (PI3K-C2α), which generates phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphates, plays crucial roles in angiogenesis, by analyzing PI3K-C2α knock-out mice. The PI3K-C2α actions are mediated at least in part through its participation in the internalization of VEGF receptor-2 and sphingosine-1-phosphate receptor S1P1 and thereby their signaling … on endosomes. TGFβ, which is also an essential angiogenic factor, signals via the serine/threonine kinase receptor complex to induce phosphorylation of Smad2 and Smad3 (Smad2/3). SARA (Smad anchor for receptor activation) protein, which is localized in early endosomes through its FYVE domain, is required for Smad2/3 signaling. In the present study, we showed that PI3K-C2α knockdown nearly completely abolished TGFβ1-induced phosphorylation and nuclear translocation of Smad2/3 in vascular endothelial cells (ECs). PI3K-C2α was necessary for TGFβ-induced increase in phosphatidylinositol 3,4-bisphosphates in the plasma membrane and TGFβ receptor internalization into the SARA-containing early endosomes, but not for phosphatidylinositol 3-phosphate enrichment or localization of SARA in the early endosomes. PI3K-C2α was also required for TGFβ receptor-mediated formation of SARA-Smad2/3 complex. Inhibition of dynamin, which is required for the clathrin-dependent receptor endocytosis, suppressed both TGFβ receptor internalization and Smad2/3 phosphorylation. TGFβ1 stimulated Smad-dependent VEGF-A expression, VEGF receptor-mediated EC migration, and capillary-like tube formation, which were all abolished by either PI3K-C2α knockdown or a dynamin inhibitor. Finally, TGFβ1-induced microvessel formation in Matrigel plugs was greatly attenuated in EC-specific PI3K-C2α-deleted mice. These observations indicate that PI3K-C2α plays the pivotal role in TGFβ receptor endocytosis and thereby Smad2/3 signaling, participating in angiogenic actions of TGFβ. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. 続きを見る

URL:

http://hdl.handle.net/2297/41360