論文

国際誌
2021年3月4日

Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells.

Scientific reports
  • Shota Shimizu
  • ,
  • Kazuaki Yoshioka
  • ,
  • Sho Aki
  • ,
  • Yoh Takuwa

11
1
開始ページ
5199
終了ページ
5199
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41598-021-84548-4

The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) plays a crucial role in angiogenesis at least in part through participating in endocytosis and, thereby, endosomal signaling of several cell surface receptors including VEGF receptor-2 and TGFβ receptor in vascular endothelial cells (ECs). The Notch signaling cascade regulates many cellular processes including cell proliferation, cell fate specification and differentiation. In the present study, we explored a role of PI3K-C2α in Delta-like 4 (Dll4)-induced Notch signaling in ECs. We found that knockdown of PI3K-C2α inhibited Dll4-induced generation of the signaling molecule Notch intracellular domain 1 (NICD1) and the expression of Notch1 target genes including HEY1, HEY2 and NOTCH3 in ECs but not in vascular smooth muscle cells. PI3K-C2α knockdown did not inhibit Dll4-induced endocytosis of cell surface Notch1. In contrast, PI3K-C2α knockdown as well as clathrin heavy chain knockdown impaired endocytosis of Notch1-cleaving protease, γ-secretase complex, with the accumulation of Notch1 at the perinuclear endolysosomes. Pharmacological blockage of γ-secretase also induced the intracellular accumulation of Notch1. Taken together, we conclude that PI3K-C2α is required for the clathrin-mediated endocytosis of γ-secretase complex, which allows for the cleavage of endocytosed Notch1 by γ-secretase complex at the endolysosomes to generate NICD1 in ECs.

リンク情報
DOI
https://doi.org/10.1038/s41598-021-84548-4
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33664344
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933152
ID情報
  • DOI : 10.1038/s41598-021-84548-4
  • PubMed ID : 33664344
  • PubMed Central 記事ID : PMC7933152

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