Nuclear targeting of transforming growth factor-b-activated smad complexes

被引:54
作者
Chen, HB
Rud, JG
Lin, K
Xu, L
机构
[1] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA
[2] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA
关键词
D O I
10.1074/jbc.M500362200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Upon stimulation by the transforming growth factor b (TGF-b), Smad2 and Smad3 are phosphorylated at their C termini and assemble into stable heteromeric complexes with Smad4. These complexes are the functional entities that translocate into the nucleus and regulate the expression of TGF-b target genes. Here we report that the TGF-b- activated phospho-Smad3/ Smad4 complex utilizes an importin-independent mechanism for nuclear import and engages different nucleoporins for nuclear import compared with the monomeric Smad4. Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. We also demonstrate that the binding of phospho-Smad3 to Smad4 prevents Smad4 from interacting with the nuclear export receptor chromosome region maintenance 1. In this way, TGF-b signaling suppresses nuclear export of Smad4 by chromosome region maintenance 1 and thereby targets Smad4 into the nucleus. Indeed tumorigenic mutations in Smad4 that affect its interaction with Smad2 or Smad3 impair nuclear accumulation of Smad4 in response to TGF-b.
引用
收藏
页码:21329 / 21336
页数:8
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