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

被引：692

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

共 16 条

[1] New Insights into mTOR Signaling: mTORC2 and Beyond [J].

Alessi, Dario R. ;

Pearce, Laura R. ;

Garcia-Martinez, Juan M. .

SCIENCE SIGNALING, 2009, 2 (67) :pe27

[2]

Carracedo A, 2008, J CLIN INVEST, V118, P3065, DOI [10.1172/JCI34739, 10.1172/jCI34739]

[3] Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism [J].

Charalambous, M ;

Smith, FM ;

Bennett, WR ;

Crew, TE ;

Mackenzie, F ;

Ward, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (14) :8292-8297

[4] Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation [J].

Choo, Andrew Y. ;

Yoon, Sang-Oh ;

Kim, Sang Gyun ;

Roux, Philippe P. ;

Blenis, John .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (45) :17414-17419

[5] Glucose Addiction of TSC Null Cells Is Caused by Failed mTORC1-Dependent Balancing of Metabolic Demand with Supply [J].

Choo, Andrew Y. ;

Kim, Sang Gyun ;

Heiden, Matthew G. Vander ;

Mahoney, Sarah J. ;

Vu, Hieu ;

Yoon, Sang-Oh ;

Cantley, Lewis C. ;

Blenis, John .

MOLECULAR CELL, 2010, 38 (04) :487-499

[6] Not all substrates are treated equally Implications for mTOR, rapamycin-resistance and cancer therapy [J].

Choo, Andrew Y. ;

Blenis, John .

CELL CYCLE, 2009, 8 (04) :567-572

[7] Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-Deficient glioblastoma [J].

Cloughesy, Tim F. ;

Yoshimoto, Koji ;

Nghiemphu, Phioanh ;

Brown, Kevin ;

Dang, Julie ;

Zhu, Shaojun ;

Hsueh, Teli ;

Chen, Yinan ;

Wang, Wei ;

Youngkin, David ;

Liau, Linda ;

Martin, Neil ;

Becker, Don ;

Bergsneider, Marvin ;

Lai, Albert ;

Green, Richard ;

Oglesby, Tom ;

Koleto, Michael ;

Trent, Jeff ;

Horvath, Steve ;

Mischel, Paul S. ;

Mellinghoff, Ingo K. ;

Sawyers, Charles L. .

PLOS MEDICINE, 2008, 5 (01) :139-151

[8] The Pharmacology of mTOR Inhibition [J].

Guertin, David A. ;

Sabatini, David M. .

SCIENCE SIGNALING, 2009, 2 (67) :pe24

[9] Phosphorylation of Grb10 by mitogen-activated protein kinase:: Identification of Ser150 and Ser476 of human Grb10ζ as major phosphorylation site [J].

Langlais, P ;

Wang, CH ;

Dong, LQ ;

Carroll, CA ;

Weintraub, ST ;

Liu, F .

BIOCHEMISTRY, 2005, 44 (24) :8890-8897

[10] Grb10: More than a simple adaptor protein [J].

Lim, MA ;

Riedel, H ;

Liu, F .

FRONTIERS IN BIOSCIENCE-LANDMARK, 2004, 9 :387-403

← 1 2 →