Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.

Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
Mol Cell Biol. 2015 35 (7): 1299-313

PMID: 25582201 · PMCID: PMC4355541 · DOI:10.1128/MCB.00306-14

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

MeSH Terms (21)

Adaptor Proteins, Signal Transducing Animals Carrier Proteins Cell Proliferation Cells, Cultured Endothelial Cells Gene Deletion Humans Human Umbilical Vein Endothelial Cells Mechanistic Target of Rapamycin Complex 2 Mice Multiprotein Complexes Neovascularization, Physiologic Phosphorylation Protein Kinase C-alpha Proto-Oncogene Proteins c-akt Rapamycin-Insensitive Companion of mTOR Protein Regulatory-Associated Protein of mTOR Signal Transduction TOR Serine-Threonine Kinases Vascular Endothelial Growth Factor A

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