TBC1D7 Is a Third Subunit of the TSC1-TSC2 Complex Upstream of mTORC1

被引：495

作者：

Dibble, Christian C. ^{[1
]}

Elis, Winfried ^{[2
]}

Menon, Suchithra ^{[1
]}

Qin, Wei ^{[4
,5
]}

Klekota, Justin ^{[2
]}

Asara, John M. ^{[3
,5
]}

Finan, Peter M. ^{[2
]}

Kwiatkowski, David J. ^{[4
,5
]}

Murphy, Leon O. ^{[2
]}

Manning, Brendan D. ^{[1
]}

机构：

[1] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[2] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[3] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Translat Med Div, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

来源：

MOLECULAR CELL | 2012年 / 47卷 / 04期

关键词：

TUBEROUS SCLEROSIS COMPLEX; CELL-GROWTH; GENE-PRODUCTS; AMINO-ACIDS; TUMOR SUPPRESSORS; MAMMALIAN TARGET; PROTEIN COMPLEX; RAG GTPASES; S6; KINASE; TSC1; GENE;

D O I：

10.1016/j.molcel.2012.06.009

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：

The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is 1:he functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.

引用

页码：535 / 546

页数：12

共 50 条

[1] The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination [J].

Benvenuto, G ;

Li, SW ;

Brown, SJ ;

Braverman, R ;

Vass, WC ;

Cheadle, JP ;

Halley, DJJ ;

Sampson, JR ;

Wienecke, R ;

DeClue, JE .

ONCOGENE, 2000, 19 (54) :6306-6316

[2] Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified [J].

Camposano, S. E. ;

Greenberg, E. ;

Kwiatkowski, D. J. ;

Thiele, E. A. .

ANNALS OF HUMAN GENETICS, 2009, 73 :141-146

[3] 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

[4] The tuberous sclerosis complex [J].

Crino, Peter B. ;

Nathanson, Katherine L. ;

Henske, Elizabeth Petri .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (13) :1345-1356

[5] Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders [J].

Ehninger, Dan ;

Silva, Alcino J. .

TRENDS IN MOLECULAR MEDICINE, 2011, 17 (02) :78-87

[6] Illuminating the functional and structural repertoire of human TBC/ RABGAPs [J].

Frasa, Marieke A. M. ;

Koessmeier, Katja T. ;

Ahmadian, M. Reza ;

Braga, Vania M. M. .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2012, 13 (02) :67-73

[7] The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway [J].

Frittoli, Emanuela ;

Palamidessi, Andrea ;

Pizzigoni, Alessandro ;

Lanzetti, Letizia ;

Garre, Massimiliano ;

Troglio, Flavia ;

Troilo, Albino ;

Fukuda, Mitsunori ;

Di Fiore, Pier Paolo ;

Scita, Giorgio ;

Confalonieri, Stefano .

MOLECULAR BIOLOGY OF THE CELL, 2008, 19 (04) :1304-1316

[8] TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth [J].

Gao, XS ;

Pan, DJ .

GENES & DEVELOPMENT, 2001, 15 (11) :1383-1392

[9] Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 [J].

Garami, A ;

Zwartkruis, FJT ;

Nobukuni, T ;

Joaquin, M ;

Roccio, M ;

Stocker, H ;

Kozma, SC ;

Hafen, E ;

Bos, JL ;

Thomas, G .

MOLECULAR CELL, 2003, 11 (06) :1457-1466

[10] Tandem affinity purification and identification of the human TSC1 protein complex [J].

Guo, Longhua ;

Ying, Wantao ;

Zhang, Jiyang ;

Yuan, Yanzhi ;

Qian, Xiaohong ;

Wang, Jian ;

Yang, Xiaoming ;

He, Fuchu .

ACTA BIOCHIMICA ET BIOPHYSICA SINICA, 2010, 42 (04) :266-273

← 1 2 3 4 5 →