Function
SMAD4 binds to receptor-regulated SMADs (R-SMADs), such as SMAD1 or SMAD2 and facilitates the translocation of the heteromeric complex into the nucleus. SMAD4 may form heterotrimeric, heterohexameric or heterodimeric complexes with R-SMADs.
In the nucleus the heteromeric complex binds promoters and interact with transcriptional activators. SMAD3/SMAD4 complexes can directly bind the SBE (Smad-binding DNA element), which is a four-base-pair sequence 5′-GTCT-3' or the complement 5′-AGAC-3′. These associations are weak and require additional transcription factors such as members of the AP-1 family, TFE3 and FoxG1 to regulate gene expression.
Many TGFβ ligands use this pathway and subsequently SMAD4 is involved in many cell functions such as differentiation, apoptosis, gastrulation, embryonic development and the cell cycle.
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