Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor β signaling.
Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor β signaling.
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DOI：
10.1091/mbc.e15-07-0545
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发表时间：
2015-11-01
影响因子：
3.3
通讯作者：
Leof EB
中科院分区：
文献类型：
--
作者：
Wilkes MC;Repellin CE;Kang JH;Andrianifahanana M;Yin X;Leof EB
分选连接蛋白9（SNX9）显示通过介导磷酸化Smad3与输入蛋白8和核膜的缔合来区分Smad3和Smad2核递送。虽然SNX9的缺乏对转化生长因子β受体活性或Smad2信号传导的影响可以忽略不计，但Smad3依赖性靶点和表型受到抑制。转化生长因子β（TGFβ）是一种多效性蛋白质，基本上由所有细胞类型和原代组织分泌。虽然TGFβ的作用反映了许多信号网络的活性，但TGFβ反应的主要介导物是Smad蛋白。在受体激活后，这些胞质蛋白形成异源寡聚复合物，其易位到细胞核并影响基因转录。在这里，通过生物学，生物化学和免疫荧光方法，分选连接蛋白9（SNX9）被确定为Smad3依赖性反应所需的。SNX9独立于Smad2或Smad4与磷酸化（p）Smad3相互作用，并促进比独立于配体观察到的更快的核递送。虽然SNX9不结合核孔蛋白Nup153或Nup214或一些β输入蛋白（Imp7或Impβ），但它介导pSmad3与Imp8和核膜的结合。这促进了pSmad3而不是SNX9的核转位。
Sorting nexin 9 (SNX9) is shown to differentiate Smad3 from Smad2 nuclear delivery by mediating the association of phosphorylated Smad3 with importin 8 and the nuclear membrane. While the absence of SNX9 had negligible effects on transforming growth factor β receptor activity or Smad2 signaling, Smad3-dependent targets and phenotypes were inhibited. Transforming growth factor β (TGFβ) is a pleiotropic protein secreted from essentially all cell types and primary tissues. While TGFβ’s actions reflect the activity of a number of signaling networks, the primary mediator of TGFβ responses are the Smad proteins. Following receptor activation, these cytoplasmic proteins form hetero-oligomeric complexes that translocate to the nucleus and affect gene transcription. Here, through biological, biochemical, and immunofluorescence approaches, sorting nexin 9 (SNX9) is identified as being required for Smad3-dependent responses. SNX9 interacts with phosphorylated (p) Smad3 independent of Smad2 or Smad4 and promotes more rapid nuclear delivery than that observed independent of ligand. Although SNX9 does not bind nucleoporins Nup153 or Nup214 or some β importins (Imp7 or Impβ), it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates nuclear translocation of pSmad3 but not SNX9.