Fig. 2

NEDD4 family members in the BMP/Smad and TGF-β/Smad pathways. BMP/Smad pathway: BMP binding to its receptors activates the phosphorylation of Smads1, 5, and 8 (R-Smads), which can be inhibited by Smurf2 and ITCH. Phosphorylated R-Smads form a complex with Smad4 (Co-Smad), translocating to the nucleus to activate key osteoblastogenic transcription factors, such as Runx2 and Osterix. Smurf1 inhibits Co-Smad, while Runx2 is regulated by Smurf1(inhibition), WWP1 (inhibition), and WWP2 (activation). TGF-β/Smad pathway: TGF-β binding to its receptor phosphorylates Smad2 and Smad3 (R-Smads), which then associate with Smad4 (Co-Smad) and translocate to the nucleus, where they recruit co-factors to activate TGF-β target gene transcription. R-Smads are inhibited by NEDD4L, and Smad4 is inhibited by WWP1