PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis
Journal article
Davies, Elizabeth M., Gurung, Rajendra, Le, Kai Qin, Roan, Katherine T. T., Harvey, Richard P., Mitchell, Geraldine M., Schwarz, Quenten and Mitchell, Christina A.. (2023). PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis. Science Advances. 9(13), p. Article eadd6911. https://doi.org/10.1126/sciadv.add6911
Authors | Davies, Elizabeth M., Gurung, Rajendra, Le, Kai Qin, Roan, Katherine T. T., Harvey, Richard P., Mitchell, Geraldine M., Schwarz, Quenten and Mitchell, Christina A. |
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Abstract | 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)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 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)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing β-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored β-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic β-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for β-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis. |
Year | 2023 |
Journal | Science Advances |
Journal citation | 9 (13), p. Article eadd6911 |
Publisher | American Association for the Advancement of Science |
ISSN | 2375-2548 |
Digital Object Identifier (DOI) | https://doi.org/10.1126/sciadv.add6911 |
PubMed ID | 37000875 |
Scopus EID | 2-s2.0-85151378240 |
PubMed Central ID | PMC10065449 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-23 |
Funder | National Health and Medical Research Council (NHMRC) |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 31 Mar 2023 |
Publication process dates | |
Accepted | 24 Feb 2023 |
Deposited | 01 Apr 2025 |
Grant ID | GNT1010368 |
Additional information | Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC) (https://creativecommons.org/licenses/by-nc/4.0/). |
https://acuresearchbank.acu.edu.au/item/91883/pi-4-5-p2-dependent-regulation-of-endothelial-tip-cell-specification-contributes-to-angiogenesis
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Publisher's version
OA_Davies_2023_PI_4_5_P2_dependent_regulation.pdf | |
License: CC BY-NC 4.0 | |
File access level: Open |
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