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.
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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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