Abstract
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.
Highlights
Endoderm[16,17]
It is reported that TGFβ mediated Smad2/Smad[4] or Smad3/Smad[4] oligomers translocate into the nucleus through direct interaction with nuclear pore complex CAN/NUP214 and NUP153, while Smad3/Smad[4] could enter nucleus through an importin-β 1 and Ran dependent mechanism[25,26,27,28]
To investigate whether preferential localization of Smad[3] in the nucleus is unique to human ESCs, we repeated the experiment in HEK 293 cells and human embryonic fibroblast (HEF) cells
Summary
Endoderm[16,17]. These phenotypes are reminiscent with those observations in embryos with decreased levels of Nodal[17]. We present evidence and show that in contrast to Smad[2], which resides in the cytoplasm, a large pool of Smad[3] preferentially distributes in the nucleus This static nuclear distribution of Smad[3] is TGFβ signaling-, C-terminal phosphorylation- and Smad4-independent. Smad[3] is important for normal neural specification, an early developmental event supposes to be inhibited by TGFβ related signals. This neural potentiation role of Smad[3] depends on its nuclear distribution property which is unrelated to TGFβ activation. We conclude that Smad[3] differs from Smad[2] in multiple aspects, including static subcellular localization, signaling relaying capability and role in early embryonic development
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
