A model for mono-ubiquitination in TGF-β signaling. Upon TGF-β stimulation, Smad3 is phosphorylated at sites in both the linker and the C-terminal tail. Phosphorylation of T179 in the linker region potentiates Smurf2 binding and the subsequent mono-ubiquitination. Smad3 mono-ubiquitination can be reversed by USP15. On the other hand, mono-ubiquitination of Smad4 is induced by Ecto/Tif1γ, and reversed by FAM/USP9x. The unmodified Smad3 and Smad4 form a DNA binding complex that regulates target gene expression whereas mono-ubiquitinated Smad3 or Smad4 inhibits or disrupts the Smad complex formation.