Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex

被引：68

作者：

Nellist, M

Sancak, O

Goedbloed, MA

Rohe, C

van Netten, D

Mayer, K

Tucker-Williams, A

van den Ouweland, AMW

Halley, DJJ

机构：

[1] Erasmus MC, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands

[2] Med Genet Lab, D-82152 Martinsried, Germany

[3] Univ Texas, Sch Med, Dept Pediat, Houston, TX USA

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2005年 / 13卷 / 01期

关键词：

tuberin; hamartin; tuberous sclerosis;

D O I：

10.1038/sj.ejhg.5201276

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：

Tuberous sclerosis is an autosomal dominant human disorder caused by inactivating mutations to either the TSC1 or TSC2 tumour suppressor gene. Hamartin and tuberin, the TSC1 and TSC2 gene products, interact and the tuberin-hamartin complex inhibits cell growth by antagonising signal transduction to downstream effectors of the mammalian target of rapamycin (mTOR) through the small GTPase rheb. Previously, we showed that pathogenic tuberin amino-acid substitutions disrupt the tuberin-hamartin complex. Here, we investigate how these mutations affect the role of tuberin in the control of signal transduction through mTOR. Our data indicate that specific amino-acid substitutions have distinct effects on tuberin function.

引用

收藏

页码：59 / 68

页数：10

相关论文

共 30 条

[1] Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1 cyclin B [J].

Astrinidis, A ;

Senapedis, W ;

Coleman, TR ;

Henske, EP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (51) :51372-51379

[2] 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

[3] Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner [J].

Castro, AF ;

Rebhun, JF ;

Clark, GJ ;

Quilliam, LA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (35) :32493-32496

[4] 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

[5]

GOMEZ MG, 1991, DEV PERSPECTIVES PSY

[6] Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation -: A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM) [J].

Goncharova, EA ;

Goncharov, DA ;

Eszterhas, A ;

Hunter, DS ;

Glassberg, MK ;

Yeung, RS ;

Walker, CL ;

Noonan, D ;

Kwiatkowski, DJ ;

Chou, MM ;

Panettieri, RA ;

Krymskaya, VP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (34) :30958-30967

[7] AMINO-ACID SUBSTITUTION MATRICES FROM PROTEIN BLOCKS [J].

HENIKOFF, S ;

HENIKOFF, JG .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (22) :10915-10919

[8] Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin [J].

Hodges, AK ;

Li, SW ;

Maynard, J ;

Parry, L ;

Braverman, R ;

Cheadle, JP ;

DeClue, JE ;

Sampson, JR .

HUMAN MOLECULAR GENETICS, 2001, 10 (25) :2899-2905

[9] Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling [J].

Inoki, K ;

Li, Y ;

Xu, T ;

Guan, KL .

GENES & DEVELOPMENT, 2003, 17 (15) :1829-1834

[10] Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent [J].

Jaeschke, A ;

Hartkamp, J ;

Saitoh, M ;

Roworth, W ;

Nobukuni, T ;

Hodges, A ;

Sampson, J ;

Thomas, G ;

Lamb, R .

JOURNAL OF CELL BIOLOGY, 2002, 159 (02) :217-224