Mutations Increasing Autoinhibition Inactivate Tumour Suppressors Smad2 and Smad4

Nature. 1997 Jul 3;388(6637):82-7. doi: 10.1038/40424.

Abstract

Smad2 and Smad4 are related tumour-suppressor proteins, which, when stimulated by the growth factor TGF-beta, form a complex to inhibit growth. The effector function of Smad2 and Smad4 is located in the conserved carboxy-terminal domain (C domain) of these proteins and is inhibited by the presence of their amino-terminal domains (N domain). This inhibitory function of the N domain is shown here to involve an interaction with the C domain that prevents the association of Smad2 with Smad4. This inhibitory function is increased in tumour-derived forms of Smad2 and 4 that carry a missense mutation in a conserved N domain arginine residue. The mutant N domains have an increased affinity for their respective C domains, inhibit the Smad2-Smad4 interaction, and prevent TGF beta-induced Smad2-Smad4 association and signalling. Whereas mutations in the C domain disrupt the effector function of the Smad proteins, N-domain arginine mutations inhibit SMAD signalling through a gain of autoinhibitory function. Gain of autoinhibitory function is a new mechanism for inactivating tumour suppressors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Cloning, Molecular
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Escherichia coli
  • Gene Expression Regulation
  • Genes, Tumor Suppressor*
  • Humans
  • Mutation
  • Neoplasms / genetics
  • Nerve Growth Factors
  • Saccharomyces cerevisiae / genetics
  • Signal Transduction
  • Smad Proteins
  • Smad2 Protein
  • Smad4 Protein
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / physiology
  • Xenopus
  • Xenopus Proteins*

Substances

  • DNA-Binding Proteins
  • Nerve Growth Factors
  • SMAD2 protein, human
  • SMAD4 protein, human
  • Smad Proteins
  • Smad2 Protein
  • Smad2 protein, Xenopus
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus