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.

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
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Monomeric GTP-Binding Proteins