The 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 the CD146-Rictor/mTORC2 complex
protects Rictor from ubiquitin-proteasome-mediated degradation, thereby specifically upregulating
mTORC2 activity with no intervention of the
PI3K and mTORC1 pathways. This CD146-mediated
mTORC2 activation in response to GF stimulation
promotes cell proliferation and survival. Therefore,
our findings identify a molecular mechanism by
which extracellular stimuli regulate mTORC2 activity,
linking environmental cues with mTORC2 regulation.