Figure 4. SMAD6 inhibits osteoblast differentiation by inhibiting BMP-mediated SMAD signaling (Salazar et al., 2016).
(a) BMP ligands activate BMP receptors, leading to phosphorylation of receptor-regulated SMADs (R-SMADs), which complex with SMAD4 and enter the nucleus, cooperating with RUNX2 to induce osteoblast differentiation. SMAD6 inhibits this signal by competing with SMAD4 for binding to R-SMADs, preventing nuclear translocation. (b) SMAD6 also cooperates with SMURF1, an E3 ubiquitin ligase, to induce ubiquitin-mediated proteasomal degradation of R-SMADs, BMP receptor complexes, and RUNX2.