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

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Title: CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of PI3K and mTORC1 Pathways
Authors: Xu, W
Hua, H
Chiu, Y
Li, G
Zhi, H
Yu, Z
Ren, F
Luo, Y
Cui, W
Item Type: Journal Article
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.
Issue Date: 29-Oct-2019
Date of Acceptance: 17-Sep-2019
URI: http://hdl.handle.net/10044/1/74358
DOI: https://dx.doi.org/10.1016/j.celrep.2019.09.047
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 1311
End Page: 1322.E5
Journal / Book Title: Cell Reports
Volume: 29
Issue: 5
Copyright Statement: © 2019 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Genesis Research Trust
Genesis Research Trust
Funder's Grant Number: 01069
Keywords: 0601 Biochemistry and Cell Biology
Publication Status: Published
Open Access location: https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31235-5?dgcid=raven_jbs_etoc_email
Online Publication Date: 2019-10-29
Appears in Collections:Department of Metabolism, Digestion and Reproduction