CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of PI3K and mTORC1 Pathways

Abstract

SummaryThe mechanistic target of rapamycin complex 2 (mTORC2) coordinates cell proliferation, survival and metabolism with environmental inputs, yet how extracellular stimuli such as growth factors (GFs) activate mTORC2 remains enigmatic. Here we demonstrate that, in human endothelial cells, activation of mTORC2 signaling by GFs is mediated by transmembrane cell adhesion protein CD146. Upon GF stimulation, the cytoplasmic tail of CD146 is phosphorylated, which permits its positively charged, juxtamembrane KKGK motif to interact with Rictor, the defining subunit of mTORC2. The formation of CD146-Rictor/mTORC2 complex protects Rictor from ubiquitin-proteasome-mediated degradation, thereby specifically upregulating mTORC2 activity with no intervention of PI3K and mTORC1 pathways. This CD146-mediated mTORC2 activation in response to GF stimulation promotes cell proliferation and survival. Therefore, our findings have identified a previously unknown mechanism by which extracellular stimuli regulate mTORC2 activity, linking environmental cues with mTORC2 regulation.

Keywords: mTORC2, rictor, CD146, PI3K, mTORC1, signal transduction, cell proliferation