In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs to regulate many fundamental cellular processes such as cell growth and metabolism. The mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. However, it remains enigmatic how extracellular stimuli regulates mTOR signaling, particularly for mTORC2. Here, we demonstrate that in human umbilical vein endothelial cells (HUVEC), vascular endothelial growth factor (VEGF) promotes the activation of mTORC2 signaling, exhibited as phosphorylation of Akt /PKCα/SGK1. Cell adhesion molecule CD146, as VEGFR2 co-receptor, plays the pivotal role in mediating mTORC2 activation in response to VEGF. Deletion of CD146 resulted in dramatic reduction in mTORC2 activity, without affecting other PI3K/Akt/mTOR signaling pathways, such as mTORC1 and PI3K/PDK1, indicating that CD146 specifically regulates mTORC2 activity. By means of co-immunoprecipitation (co-IP) assay, CD146 is bestowed to interact with Rictor via its juxta-membrane KKGK motif upon VEGF stimulation, CD146-Rictor (mTORC2) interaction not only stabilizes Rictor from ubiquitin-proteasome-mediated degradation but also activates mTORC2 signaling, thus promoting VEGF-induced endothelial cell proliferation and survival. Collectively, our findings have identified a previously unanticipated mechanism by which mTORC2 signaling pathway is directly under the control of extracellular stimuli, linking environmental cues with mTORC2 activity, and implicate that targeting CD146-mTORC2 axis might be a novel strategy for diseases driven by uncontrolled cell proliferation.

Citation Format: Wenyi Xu, Yongting Luo, Wei Cui. CD146-Rictor interaction reveals a pathway linking mTORC2 activation with extracellular stimuli [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A24.