Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4

Akiko Hata, Roger S. Lo, David Wotton, Giorgio Lagna and Joan Massagué ()
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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

Nature, 1997, vol. 388, issue 6637, 82-87

Abstract: 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.

Date: 1997
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DOI: 10.1038/40424

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