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

42 Pages Posted: 18 May 2019 Sneak Peek Status: Review Complete

See all articles by Wenyi Xu

Wenyi Xu

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health; China Agricultural University - College of Food Science & Nutritional Engineering

Huijuan Hua

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health; China Agricultural University - College of Biological Sciences

Yueh-Ho Chiu

Imperial College London - Institute of Reproductive and Developmental Biology

Guannan Li

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Huihan Zhi

Imperial College London - Institute of Reproductive and Developmental Biology

Zhengquan Yu

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health; China Agricultural University - College of Biological Sciences

Fazheng Ren

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health; China Agricultural University - College of Food Science & Nutritional Engineering

Yongting Luo

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Wei Cui

China Agricultural University - College of Biological Sciences

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Abstract

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

Keywords: mTORC2, rictor, CD146, PI3K, mTORC1, signal transduction, cell proliferation

Suggested Citation

Xu, Wenyi and Hua, Huijuan and Chiu, Yueh-Ho and Li, Guannan and Zhi, Huihan and Yu, Zhengquan and Ren, Fazheng and Luo, Yongting and Cui, Wei, CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of PI3K and mTORC1 Pathways (May 15, 2019). CELL-REPORTS-D-19-01775. Available at SSRN: https://ssrn.com/abstract=3388356 or http://dx.doi.org/10.2139/ssrn.3388356
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Wenyi Xu

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Beijing
China

China Agricultural University - College of Food Science & Nutritional Engineering

Beijing
China

Huijuan Hua

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Beijing
China

China Agricultural University - College of Biological Sciences

Beijing
China

Yueh-Ho Chiu

Imperial College London - Institute of Reproductive and Developmental Biology

London
United Kingdom

Guannan Li

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Beijing
China

Huihan Zhi

Imperial College London - Institute of Reproductive and Developmental Biology

London
United Kingdom

Zhengquan Yu

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Beijing
China

China Agricultural University - College of Biological Sciences

Beijing
China

Fazheng Ren

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health

Beijing
China

China Agricultural University - College of Food Science & Nutritional Engineering

Beijing
China

Yongting Luo

China Agricultural University - Beijing Advanced Innovation Center for Food Nutrition and Human Health ( email )

Beijing
China

Wei Cui (Contact Author)

China Agricultural University - College of Biological Sciences ( email )

Beijing
China

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