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

Abstract 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 endotheli...

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Autores principales:	Shota Shimizu, Kazuaki Yoshioka, Sho Aki, Yoh Takuwa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a705e20f2e1e4b4d8dbd63bd7d8c26b9
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spelling	oai:doaj.org-article:a705e20f2e1e4b4d8dbd63bd7d8c26b92021-12-02T15:52:59ZClass II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells10.1038/s41598-021-84548-42045-2322https://doaj.org/article/a705e20f2e1e4b4d8dbd63bd7d8c26b92021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84548-4https://doaj.org/toc/2045-2322Abstract 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.Shota ShimizuKazuaki YoshiokaSho AkiYoh TakuwaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shota Shimizu Kazuaki Yoshioka Sho Aki Yoh Takuwa Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
description	Abstract 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.
format	article
author	Shota Shimizu Kazuaki Yoshioka Sho Aki Yoh Takuwa
author_facet	Shota Shimizu Kazuaki Yoshioka Sho Aki Yoh Takuwa
author_sort	Shota Shimizu
title	Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
title_short	Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
title_full	Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
title_fullStr	Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
title_full_unstemmed	Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
title_sort	class ii phosphatidylinositol 3-kinase-c2α is essential for notch signaling by regulating the endocytosis of γ-secretase in endothelial cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a705e20f2e1e4b4d8dbd63bd7d8c26b9
work_keys_str_mv	AT shotashimizu classiiphosphatidylinositol3kinasec2aisessentialfornotchsignalingbyregulatingtheendocytosisofgsecretaseinendothelialcells AT kazuakiyoshioka classiiphosphatidylinositol3kinasec2aisessentialfornotchsignalingbyregulatingtheendocytosisofgsecretaseinendothelialcells AT shoaki classiiphosphatidylinositol3kinasec2aisessentialfornotchsignalingbyregulatingtheendocytosisofgsecretaseinendothelialcells AT yohtakuwa classiiphosphatidylinositol3kinasec2aisessentialfornotchsignalingbyregulatingtheendocytosisofgsecretaseinendothelialcells
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Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells

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