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

Mark Nellist; Ozgur Sancak; Miriam A Goedbloed; Christan Rohe; Diana van Netten; Karin Mayer; Aimee Tucker-Williams; Ans M W van den Ouweland; Dicky J J Halley

doi:10.1038/sj.ejhg.5201276

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

Eur J Hum Genet. 2005 Jan;13(1):59-68. doi: 10.1038/sj.ejhg.5201276.

Authors

Mark Nellist¹, Ozgur Sancak, Miriam A Goedbloed, Christan Rohe, Diana van Netten, Karin Mayer, Aimee Tucker-Williams, Ans M W van den Ouweland, Dicky J J Halley

Affiliation

¹ Department of Clinical Genetics, Erasmus MC, 3015 GE Rotterdam, The Netherlands. m.nellist@erasmusmc.nl

PMID: 15483652
DOI: 10.1038/sj.ejhg.5201276

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Phosphoinositide-Dependent Protein Kinases
Amino Acid Substitution / physiology*
Animals
Chemokine CCL26
Chemokines, CC / physiology*
Fibroblasts / metabolism
Humans
Mice
Mice, Knockout
Monomeric GTP-Binding Proteins / metabolism
Mutagenesis, Site-Directed
Mutation, Missense
Neuropeptides / metabolism
Phosphorylation
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / metabolism
Ras Homolog Enriched in Brain Protein
Repressor Proteins / physiology*
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction*
TOR Serine-Threonine Kinases
Tuberous Sclerosis / genetics
Tuberous Sclerosis / metabolism
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins / physiology*

Substances

CCL26 protein, human
Chemokine CCL26
Chemokines, CC
Neuropeptides
RHEB protein, human
Ras Homolog Enriched in Brain Protein
Repressor Proteins
TSC1 protein, human
TSC2 protein, human
Tsc1 protein, mouse
Tsc2 protein, mouse
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
Protein Kinases
MTOR protein, human
mTOR protein, mouse
3-Phosphoinositide-Dependent Protein Kinases
Protein Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Monomeric GTP-Binding Proteins