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

Cell Rep. 2019 Oct 29;29(5):1311-1322.e5. doi: 10.1016/j.celrep.2019.09.047.

Abstract

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.

Keywords: CD146; PI3K; Rictor; cell proliferation; mTORC1; mTORC2; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • CD146 Antigen / chemistry
  • CD146 Antigen / metabolism
  • Cell Proliferation / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mutant Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / drug effects
  • Proteolysis / drug effects
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Signal Transduction* / drug effects
  • Ubiquitin / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • CD146 Antigen
  • Intercellular Signaling Peptides and Proteins
  • MCAM protein, human
  • Mutant Proteins
  • RICTOR protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proteasome Endopeptidase Complex