Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4
Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4
复制标题
DOI：
10.1038/40424
复制
发表时间：
1997-07-03
期刊：
影响因子：
64.8
通讯作者：
Massague, J
中科院分区：
文献类型：
--
作者：
Hata, A;Lo, RS;Massague, J
Smad2和Smad4是相关的肿瘤抑制蛋白（1,2），当受到生长因子tgf - β的刺激时，形成复合物抑制生长(3)。Smad2和Smad4的效应功能位于这些蛋白的保守羧基末端结构域（C结构域），并被它们的氨基末端结构域（N结构域）的存在所抑制（4,5）。N结构域的这种抑制功能涉及到与C结构域的相互作用，从而阻止Smad2与Smad4的结合。这种抑制功能在肿瘤来源的Smad2和4中增加，这些Smad2和4在保守的N结构域精氨酸残基中携带错义突变。突变的N结构域对各自的C结构域具有更高的亲和力，抑制Smad2-Smad4相互作用，并阻止TGF β诱导的Smad2-Smad4关联和信号传导。C结构域的突变破坏Smad蛋白的效应功能，而n结构域精氨酸突变通过自身抑制功能的g-ain抑制Smad信号。获得自身抑制功能是使肿瘤抑制因子失活的新机制。
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.