TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling.
TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling.
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DOI：
10.1091/mbc.e15-04-0203
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发表时间：
2015-10-01
影响因子：
3.3
通讯作者：
Henis YI
中科院分区：
文献类型：
--
作者：
Tazat K;Hector-Greene M;Blobe GC;Henis YI
对t -β riii与信号传导TGF-β受体相互作用的研究表明，t -β riii的同质寡聚是间接的，主要依赖于与GIPC支架的相互作用。t - β ri和II独立结合t - β riii，与t - β ri - t - β rii复合物形成竞争，通过独立于t - β riii外结构域脱落的机制抑制Smad2/3信号。转化生长因子-β (TGF-β)受体寡聚化在信号传导中具有重要作用。I型和II型（TβRI和TβRII） TGF-β受体之间的复合物形成已被很好地表征，并且对信号转导至关重要。然而，它们与活细胞中III型TGF-β辅助受体（t -β riii）的相互作用及其对TGF-β信号传导的影响的研究尚缺乏。本研究通过结合igg介导的TGF-β受体的补丁/固定化和光漂白后共表达受体的横向扩散的荧光恢复研究，研究了TβRIII与TβRI和TβRII在活细胞中的同质和异质相互作用。我们的研究表明，t - β riii的同质寡聚化是间接的，依赖于其与支架蛋白（主要是GIPC）的细胞质结构域相互作用。我们发现TβRII和TβRI独立结合TβRIII，而TβRIII增强了TβRI/TβRII的结合，这表明TβRI和TβRII同时结合TβRIII，但不是以复合物的形式结合。在MDA-MB-231细胞系中，TβRIII的表达抑制TGF-β介导的Smad2/3信号通路，这种作用依赖于TβRIII细胞质结构域，不需要TβRIII外畴脱落。我们提出t -β ri和t -β rii与t -β riii的独立结合与t -β ri / t -β rii信号复合物形成竞争，从而抑制TGF-β介导的Smad信号传导。
Study of the TβRIII interaction with the signaling TGF-β receptors shows that TβRIII homo-oligomerization is indirect, depending largely on interactions with GIPC scaffolds. TβRI and II bind independently to TβRIII, competing with TβRI-TβRII complex formation and inhibiting Smad2/3 signaling by a mechanism independent of TβRIII ectodomain shedding. Transforming growth factor-β (TGF-β) receptor oligomerization has important roles in signaling. Complex formation among type I and type II (TβRI and TβRII) TGF-β receptors is well characterized and is essential for signal transduction. However, studies on their interactions with the type III TGF-β coreceptor (TβRIII) in live cells and their effects on TGF-β signaling are lacking. Here we investigated the homomeric and heteromeric interactions of TβRIII with TβRI and TβRII in live cells by combining IgG-mediated patching/immobilization of a given TGF-β receptor with fluorescence recovery after photobleaching studies on the lateral diffusion of a coexpressed receptor. Our studies demonstrate that TβRIII homo-oligomerization is indirect and depends on its cytoplasmic domain interactions with scaffold proteins (mainly GIPC). We show that TβRII and TβRI bind independently to TβRIII, whereas TβRIII augments TβRI/TβRII association, suggesting that TβRI and TβRII bind to TβRIII simultaneously but not as a complex. TβRIII expression inhibited TGF-β–mediated Smad2/3 signaling in MDA-MB-231 cell lines, an effect that depended on the TβRIII cytoplasmic domain and did not require TβRIII ectodomain shedding. We propose that independent binding of TβRI and TβRII to TβRIII competes with TβRI/TβRII signaling complex formation, thus inhibiting TGF-β–mediated Smad signaling.