Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling

被引：683

作者：

Yu, Yonghao ^{[1
]}

Yoon, Sang-Oh ^{[1
]}

Poulogiannis, George ^{[2
]}

Yang, Qian ^{[1
,3
]}

Ma, Xiaoju Max ^{[1
]}

Villen, Judit ^{[1
]}

Kubica, Neil ^{[1
]}

Hoffman, Gregory R. ^{[1
]}

Cantley, Lewis C. ^{[2
]}

Gygi, Steven P. ^{[1
]}

Blenis, John ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[2] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA

[3] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA

来源：

SCIENCE | 2011年 / 332卷 / 6035期

关键词：

INHIBITION; DISRUPTION; RESISTANCE; ACTIVATION; KINASE; LEADS;

D O I：

10.1126/science.1199484

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.

引用

页码：1322 / 1326

页数：5

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