Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification

• Published in: Scientific reports 2016-02, Vol.6 (1), p.21602-21602, Article 21602
• Main Authors: Liu, Ling, Liu, Xu, Ren, Xudong, Tian, Yue, Chen, Zhenyu, Xu, Xiangjie, Du, Yanhua, Jiang, Cizhong, Fang, Yujiang, Liu, Zhongliang, Fan, Beibei, Zhang, Quanbin, Jin, Guohua, Yang, Xiao, Zhang, Xiaoqing
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/80/86; Active Transport, Cell Nucleus; Animals; Base Sequence; Body Patterning; Carcinogenesis - metabolism; Cell Lineage; Cell Nucleus - metabolism; Conserved Sequence; HEK293 Cells; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; Mice; Mice, Inbred NOD; Mice, SCID; multidisciplinary; Protein Binding; Protein Multimerization; Response Elements; Science; Signal Transduction; Smad2 Protein - physiology; Smad3 Protein - physiology; Teratoma - metabolism; Teratoma - pathology; Transforming Growth Factor beta - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21602

The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.