CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways.
Amino Acid Motifs
CD146 Antigen
/ chemistry
Cell Proliferation
/ drug effects
Human Umbilical Vein Endothelial Cells
/ drug effects
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
CD146
PI3K
Rictor
cell proliferation
mTORC1
mTORC2
signal transduction
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 10 2019
29 10 2019
Historique:
received:
06
05
2019
revised:
09
08
2019
accepted:
17
09
2019
entrez:
31
10
2019
pubmed:
31
10
2019
medline:
26
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31665642
pii: S2211-1247(19)31235-5
doi: 10.1016/j.celrep.2019.09.047
pii:
doi:
Substances chimiques
CD146 Antigen
0
Intercellular Signaling Peptides and Proteins
0
MCAM protein, human
0
Mutant Proteins
0
RICTOR protein, human
0
Rapamycin-Insensitive Companion of mTOR Protein
0
Ubiquitin
0
Vascular Endothelial Growth Factor A
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1311-1322.e5Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.