Regulation of TORC1 in Response to Amino Acid Starvation via Lysosomal Recruitment of TSC2

被引：362

作者：

Demetriades, Constantinos ^{[1
]}

Doumpas, Nikolaos ^{[1
]}

Teleman, Aurelio A. ^{[1
]}

机构：

[1] German Canc Res Ctr, D-69120 Heidelberg, Germany

来源：

CELL | 2014年 / 156卷 / 04期

基金：

欧洲研究理事会;

关键词：

ACTIVATING PROTEIN COMPLEX; RAG GTPASES; TSC1-TSC2; COMPLEX; GAP ACTIVITY; MTOR; KINASE; TUBERIN; RHEB; DEPRIVATION; SUFFICIENCY;

D O I：

10.1016/j.cell.2014.01.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1.

引用

页码：786 / 799

页数：14

共 35 条

[21]

Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome [J].

Menon, Suchithra ;

Dibble, Christian C. ;

Talbott, George ;

Hoxhaj, Gerta ;

Valvezan, Alexander J. ;

Takahashi, Hidenori ;

Cantley, Lewis C. ;

Manning, Brendan D. .

CELL, 2014, 156 (04) :771-785

[22]

Amino Acid Deprivation Inhibits TORC1 Through a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr1 [J].

Panchaud, Nicolas ;

Peli-Gulli, Marie-Pierre ;

De Virgilio, Claudio .

SCIENCE SIGNALING, 2013, 6 (277) :ra42

[23]

mTOR Signalling in Health and Disease [J].

Proud, Christopher G. .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2011, 39 :431-436

[24]

Regulation of the small GTPase Rheb by amino acids [J].

Roccio, M ;

Bos, JL ;

Zwartkruis, FJT .

ONCOGENE, 2006, 25 (05) :657-664

[25]

The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 [J].

Sancak, Yasemin ;

Peterson, Timothy R. ;

Shaul, Yoav D. ;

Lindquist, Robert A. ;

Thoreen, Carson C. ;

Bar-Peled, Liron ;

Sabatini, David M. .

SCIENCE, 2008, 320 (5882) :1496-1501

[26]

Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids [J].

Sancak, Yasemin ;

Bar-Peled, Liron ;

Zoncu, Roberto ;

Markhard, Andrew L. ;

Nada, Shigeyuki ;

Sabatini, David M. .

CELL, 2010, 141 (02) :290-303

[27]

MP1: A MEK binding partner that enhances enzymatic activation of the MAP kinase cascade [J].

Schaeffer, HJ ;

Catling, AD ;

Eblen, ST ;

Collier, LS ;

Krauss, A ;

Weber, MJ .

SCIENCE, 1998, 281 (5383) :1668-1671

[28]

The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses [J].

Smith, EM ;

Finn, SG ;

Tee, AR ;

Browne, G ;

Proud, CG .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (19) :18717-18727

[29]

Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb [J].

Tee, AR ;

Manning, BD ;

Roux, PP ;

Cantley, LC ;

Blenis, J .

CURRENT BIOLOGY, 2003, 13 (15) :1259-1268

[30]

Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction [J].

Teis, D ;

Wunderlich, W ;

Huber, LA .

DEVELOPMENTAL CELL, 2002, 3 (06) :803-814

← 1 2 3 4 →