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Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4

Author

Listed:
  • Akiko Hata

    (*Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center)

  • Roger S. Lo

    (*Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center)

  • David Wotton

    (*Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center)

  • Giorgio Lagna

    (†Laboratory of Molecular Embryology, The Rockefeller University)

  • Joan Massagué

    (*Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center)

Abstract

Smad2 and Smad4 are related tumour-suppressor proteins1,2, which, when stimulated by the growth factor TGF-β, form a complex to inhibit growth3. 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)4,5. 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 TGFβ-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.

Suggested Citation

  • Akiko Hata & Roger S. Lo & David Wotton & Giorgio Lagna & Joan Massagué, 1997. "Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4," Nature, Nature, vol. 388(6637), pages 82-87, July.
    • Handle: RePEc:nat:nature:v:388:y:1997:i:6637:d:10.1038_40424
    DOI: 10.1038/40424
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