biostudies-literatureUnknown9(13)Davies EMDynamic 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 incScience advanceseadd6911https://www.ebi.ac.uk/biostudies/studies/S-EPMC10065449biostudies-literaturePI(4,5)P₂-dependent regulation of endothelial tip cell specification contributes to angiogenesis.PMC10065449Le KQRoan KTTSchwarz QMitchell CADavies EMGurung RHarvey RPMitchell GMfalsePI(4,5)P₂-dependent regulation of endothelial tip cell specification contributes to angiogenesis.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 inc2023-01-01T00:00:00Z2023 Mar2025-04-04T21:09:39.655Z2025-04-04T21:09:39.655ZS-EPMC100654493700087510.1126/sciadv.add6911