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| Item Type: | Article |
|---|---|
| Title: | PI3K-C2β limits mTORC1 signaling and angiogenic growth |
| Creators: |
Kobialka, P.  ORCID: https://orcid.org/0000-0003-4765-168X, Llena, J. ORCID: https://orcid.org/0000-0002-5648-2606, Deleyto-Seldas, N. ORCID: https://orcid.org/0009-0002-0270-7336, Munar-Gelabert, M., Dengra, J.A., Villacampa, P. ORCID: https://orcid.org/0000-0002-2860-7475, Albinyà-Pedrós, A., Muixi, L. ORCID: https://orcid.org/0000-0002-9110-0474, Andrade, J. ORCID: https://orcid.org/0000-0002-4577-8620, van Splunder, H., Angulo-Urarte, A. ORCID: https://orcid.org/0000-0002-8024-814X, Potente, M. ORCID: https://orcid.org/0000-0002-5689-0036, Grego-Bessa, J. ORCID: https://orcid.org/0000-0002-0938-2346, Castillo, S.D. ORCID: https://orcid.org/0000-0002-7007-3155, Vanhaesebroeck, B. ORCID: https://orcid.org/0000-0002-7074-3673, Efeyan, A. ORCID: https://orcid.org/0000-0002-3806-6799 and Graupera, M. ORCID: https://orcid.org/0000-0003-4608-4185
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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. |
| 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 |
| External Fulltext: | View full text on external repository or document server |
| PubMed: | View item in PubMed |
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