CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways.
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.
['Xu|Wenyi|W|', 'Hua|Huijuan|H|', 'Chiu|Yueh-Ho|YH|', 'Li|Guannan|G|', 'Zhi|Huihan|H|', 'Yu|Zhengquan|Z|', 'Ren|Fazheng|F|', 'Luo|Yongting|Y|', 'Cui|Wei|W|']
D020816:Amino Acid Motifs D051929:CD146 Antigen D049109:Cell Proliferation D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D000076222:Mechanistic Target of Rapamycin Complex 1 D000076225:Mechanistic Target of Rapamycin Complex 2 D050505:Mutant Proteins D019869:Phosphatidylinositol 3-Kinases D046988:Proteasome Endopeptidase Complex D011485:Protein Binding D059748:Proteolysis D000076226:Rapamycin-Insensitive Companion of mTOR Protein D015398:Signal Transduction D025801:Ubiquitin D042461:Vascular Endothelial Growth Factor A
CD146 mTORC2 PI3K mTORC1 cell proliferation Rictor signal transduction