Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA USA.
Cell Biosci. 2011 Dec 28;1(1):40. doi: 10.1186/2045-3701-1-40.
Smad proteins are the intracellular mediators of transforming growth factor β (TGF-β) signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-β receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-β signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-β effect. Such spatial control of Smad ensures a tight regulation of TGF-β target genes. Several cross-talk pathways have been shown to affect TGF-β signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-β signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads.
Smad 蛋白是转化生长因子 β（TGF-β）信号转导的细胞内介质。Smads 作为转录因子发挥作用，其活性需要 TGF-β 受体激酶在羧基末端磷酸化，这些激酶嵌入细胞膜中。因此，激活的 Smads 从细胞质向细胞核的易位是 TGF-β 信号转导进入细胞核的限速步骤。另一方面，Smads 从细胞核输出会关闭 TGF-β 的作用。Smad 的这种空间控制确保了对 TGF-β 靶基因的严格调节。已经显示出几种交叉对话途径通过损害 Smad 的核易位来影响 TGF-β 信号转导，这体现了核转运过程的生物学重要性。许多实验室已经结合遗传学、生物化学和复杂的活细胞成像方法，研究了 Smad 核质易位的潜在分子机制。在过去的几年中，已经阐明了 Smad 核转运中的几个关键参与者，最重要的是携带 Smads 通过核膜的核孔蛋白和促进跨核膜运动的核孔蛋白。现在已经为进一步阐明核转运过程如何受到调节以及利用这些知识来操纵 TGF-β 信号奠定了基础。在这篇综述中，我们将讨论负责 Smad 核输入和输出的分子机制的最新理解。
