2. Academic Validation
  3. PI3K-C2β limits mTORC1 signaling and angiogenic growth

PI3K-C2β limits mTORC1 signaling and angiogenic growth

  • Sci Signal. 2023 Nov 28;16(813):eadg1913. doi: 10.1126/scisignal.adg1913.
Piotr Kobialka 1,  Judith Llena 1,  Nerea Deleyto-Seldas 2,  Margalida Munar-Gelabert 1,  Jose A Dengra 1,  Pilar Villacampa 1,  Alba Albinyà-Pedrós 1,  Laia Muixi 1,  Jorge Andrade 3 4,  Hielke van Splunder 1,  Ana Angulo-Urarte 1,  Michael Potente 3 4,  Joaquim Grego-Bessa 1,  Sandra D Castillo 1,  Bart Vanhaesebroeck 5,  Alejo Efeyan 2,  Mariona Graupera 1 6 7
Affiliations

Affiliations

  • 1 Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Barcelona, Catalonia, Spain.
  • 2 Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
  • 3 Angiogenesis & Metabolism Laboratory, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10178 Berlin, Germany.
  • 4 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
  • 5 Cancer Institute, Paul O'Gorman Building, University College London, WC1N 1EH London, UK.
  • 6 ICREA, Institució Catalana de Recerca i Estudis Avançats, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
  • 7 CIBERONC, Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain.
PMID: 38015911 DOI: 10.1126/scisignal.adg1913
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.

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