Fig. 3. Ubiquitylation and regulation of R-Smads.

A) Monoubiquitylation of R-Smads inhibits their association with a Smad binding element (SBE) in a target gene promoter (blue arrow). This inhibition is reversed by the deubiquitylation of R-Smads by Usp15 (green arrow) that stimulates Smad complex transcriptional activity. B) Model for potential relationship between mono- and polyubiquitylation of R-Smads. Polyubiquitylation might occur either by elongating an existing monoubiquitin via an E4 ligase or stimulated directly by an E3 ligase distinct from the one inducing monoubiquitylation (blue arrows - ubiquitin addition). Usp15 may oppose all of these reactions (green arrows - deubiquitylation). Extracellular signals or the cell-intrinsic context may regulate each of these three processes positively or negatively.