Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production

被引：30

作者：

Byun, Jun-Kyu ^{[1
]}

Park, Mihyang ^{[2
,3
]}

Yun, Jae Won ^{[4
,5
]}

Lee, Jaebon ^{[6
]}

Kim, Jae Sun ^{[6
]}

Cho, Sung Jin ^{[7
]}

Lee, You Mie ^{[1
]}

Lee, In-Kyu ^{[8
]}

Choi, Yeon-Kyung ^{[8
]}

Park, Keun-Gyu ^{[8
]}

机构：

[1] Kyungpook Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Daegu, South Korea

[2] Kyungpook Natl Univ, Grad Sch, Dept Biomed Sci, Daegu, South Korea

[3] Kyungpook Natl Univ, BK21 Plus KNU Biomed Convergence Program, Daegu, South Korea

[4] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med & Genet, Seoul, South Korea

[5] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea

[6] Sungkyunkwan Univ, Sch Med, Seoul, South Korea

[7] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu, South Korea

[8] Kyungpook Natl Univ, Kyungpook Natl Univ Hosp, Sch Med, Dept Internal Med, Daegu, South Korea

来源：

EMBO REPORTS | 2019年 / 20卷 / 06期

基金：

新加坡国家研究基金会;

关键词：

COUP-TFII; glycolysis; KRAS; lactate; mTORC1; RAG GTPASES; GROWTH; METABOLISM; RHEB; METASTASIS; EXPRESSION; PATHWAY; INSULIN; COMPLEX; BINDS;

D O I：

10.15252/embr.201847451

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：

Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS-induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK-driven lactate production in mTORC1 activation in KRAS-activated cells. KRAS/MEK-induced upregulation of the chicken ovalbumin upstream promoter transcriptional factor II (COUP-TFII) increases the expression of lactate dehydrogenase A (LDHA), resulting in lactate production and mTORC1 activation. Further, lactate inhibits the interaction of TSC2 and Rheb, leading to the cellular activation of mTORC1 irrespective of growth factor stimulation. These findings suggest that COUP-TFII is a novel oncogenic mediator, connecting KRAS signaling and glycolysis, and leading to mTORC1 activation and cellular growth.

引用

页数：11

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