PI3K-C2β limits mTORC1 signaling and angiogenic growth

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Item Type:	Article
Title:	PI3K-C2β limits mTORC1 signaling and angiogenic growth
Creators Name:	Kobialka, P., Llena, J., Deleyto-Seldas, N., Munar-Gelabert, M., Dengra, J.A., Villacampa, P., Albinyà-Pedrós, A., Muixi, L., Andrade, J., van Splunder, H., Angulo-Urarte, A., Potente, M., Grego-Bessa, J., Castillo, S.D., Vanhaesebroeck, B., Efeyan, A. and Graupera, M.
Abstract:	Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2β is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2β was a critical regulator of blood vessel growth by restricting endothelial mTORC1 signaling. Mice expressing a kinase-inactive form of PI3K-C2β displayed enlarged blood vessels without corresponding changes in endothelial cell proliferation or migration. Instead, inactivation of PI3K-C2β resulted in an increase in the size of endothelial cells, particularly in the sprouting zone of angiogenesis. Mechanistically, we showed that the aberrantly large size of PI3K-C2β mutant endothelial cells was caused by mTORC1 activation, which sustained growth in these cells. Consistently, pharmacological inhibition of mTORC1 with rapamycin normalized vascular morphogenesis in PI3K-C2β mutant mice. Together, these results identify PI3K-C2β as a crucial determinant of endothelial signaling and illustrate the importance of mTORC1 regulation during angiogenic growth.
Keywords:	Cell Proliferation, Endothelial Cells, Phosphatidylinositol 3-Kinases, Phosphatidylinositol 3-Kinases, Protein Isoforms, Signal Transduction, Animals, Mice, Mammals
Source:	Science Signaling
ISSN:	1945-0877
Publisher:	American Association for the Advancement of Science
Volume:	16
Number:	813
Page Range:	eadg1913
Date:	November 2023
Additional Information:	Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
Official Publication:	https://doi.org/10.1126/scisignal.adg1913
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