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PI3K-C2β limits mTORC1 signaling and angiogenic growth

Kobialka, Piotr; Llena, Judith; Deleyto-Seldas, Nerea; Munar-Gelabert, MARGALIDA; Dengra, JOSE A; Villacampa, ALBA; Albinyà-Pedrós, Alba; ... Graupera, Mariona; + view all (2023) PI3K-C2β limits mTORC1 signaling and angiogenic growth. Science Signaling , 16 (813) , Article eadg19. 10.1126/scisignal.adg1913. Green open access

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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.

Type: Article
Title: PI3K-C2β limits mTORC1 signaling and angiogenic growth
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scisignal.adg1913
Publisher version: https://doi.org/10.1126/scisignal.adg1913
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Animals, Mice, Cell Proliferation, Endothelial Cells, Mammals, Phosphatidylinositol 3-Kinases, Protein Isoforms, Signal Transduction
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10186576
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