mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT

被引：165

作者：

Gu, Yuchao ^{[1
,3
]}

Albuquerque, Claudio P. ^{[3
]}

Braas, Daniel ^{[1
,4
]}

Zhang, Wei ^{[10
]}

Villa, Genaro R. ^{[1
,2
,3
]}

Bi, Junfeng ^{[3
]}

Ikegami, Shiro ^{[5
]}

Masui, Kenta ^{[6
]}

Gini, Beatrice ^{[7
]}

Yang, Huijun ^{[3
]}

Gahman, Timothy C. ^{[14
]}

Shiau, Andrew K. ^{[14
]}

Cloughesy, Timothy F. ^{[11
]}

Christofk, Heather R. ^{[1
,4
]}

Zhou, Huilin ^{[3
,8
,13
]}

Guan, Kun-Liang ^{[9
,13
]}

Mischel, Paul S. ^{[3
,12
,13
]}

机构：

[1] David Geffen UCLA Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] David Geffen UCLA Sch Med, Med Scientist Training Program, Los Angeles, CA 90095 USA

[3] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[4] UCLA Metabol Ctr, Los Angeles, CA 90095 USA

[5] Chiba Canc Ctr, Div Neurol Surg, Chiba 2608717, Japan

[6] Tokyo Womens Med Univ, Dept Pathol, Tokyo 1628666, Japan

[7] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[8] UCSD Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[9] UCSD Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA

[10] UCSD Sch Med, Dept Med, La Jolla, CA 92093 USA

[11] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[12] UCSD Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[13] UCSD Sch Med, Moores Canc Ctr, La Jolla, CA 92093 USA

[14] Univ Calif San Diego, Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA

来源：

MOLECULAR CELL | 2017年 / 67卷 / 01期

关键词：

OXIDATIVE STRESS; CYSTINE/GLUTAMATE TRANSPORTER; MAMMALIAN TARGET; UP-REGULATION; CELL-GROWTH; PROMOTES; PROTEIN; INHIBITION; SUBSTRATE; RAPAMYCIN;

D O I：

10.1016/j.molcel.2017.05.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions.

引用

页码：128 / +

页数：18

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