PI(4,5)P 2 -dependent regulation of endothelial tip cell specification contributes to angiogenesis

Davies, Elizabeth M. and Gurung, Rajendra and Le, Kai Qin and Roan, Katherine T. T. and Harvey, Richard P. and Mitchell, Geraldine M. and Schwarz, Quenten and Mitchell, Christina A. (2023) PI(4,5)P 2 -dependent regulation of endothelial tip cell specification contributes to angiogenesis. Science Advances, 9 (13). ISSN 2375-2548

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Link to published document: http://doi.org/10.1126/sciadv.add6911


Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P(2) to PI(3,4,5)P(3), activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P(2) hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P(2) generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P(2), thereby releasing beta-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P(3)-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P(2) in INPP5K-siRNA cells by PIP5K1C-siRNA, restored beta-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic beta-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P(2) is critical for beta-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 27 Apr 2023 04:28
Last Modified: 27 Apr 2023 04:28
URI: http://eprints.victorchang.edu.au/id/eprint/1376

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