Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4 Journal Article
| Authors: | Hata, A.; Lo, R. S.; Wotton, D.; Lagna, G.; Massague, J. |
| Article Title: | Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4 |
| Abstract: | Smad2 and Smad4 are related tumour-suppressor proteins(1,2), which, when stimulated by the growth factor TGF-beta, form a complex to inhibit growth(3). 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 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 g-ain of autoinhibitory function. Gain of autoinhibitory function isa new mechanism for inactivating tumour suppressors. |
| Keywords: | beta |
| Journal Title: | Nature |
| Volume: | 388 |
| Issue: | 6637 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1997-07-03 |
| Start Page: | 82 |
| End Page: | 87 |
| Language: | English |
| ACCESSION: | WOS:A1997XJ14300055 |
| PROVIDER: | wos |
| PUBMED: | 9214507 |
| DOI: | 10.1038/40424 |
| Notes: | Article -- Source: Wos |
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