| First Author | Davies EM | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 13 | Pages | eadd6911 |
| PubMed ID | 37000875 | Mgi Jnum | J:334548 |
| Mgi Id | MGI:7460772 | Doi | 10.1126/sciadv.add6911 |
| Citation | Davies EM, et al. (2023) PI(4,5)P(2)-dependent regulation of endothelial tip cell specification contributes to angiogenesis. Sci Adv 9(13):eadd6911 |
| abstractText | 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. |
