It has been demonstrated previously that F-box protein Fbxl15 targets HECT-type E3 Smurf1 and forms a functionally active SCF complex for ubiquitination and proteasomal degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. Different from Fbx115, Fbxo3 targets all the Nedd4 family members for their degradation, indicating that Fbxo3 plays an important role in controlling the stability of Nedd4. Taken together, we show that Smurfl is an endogenous substrate of Fbxo3. Our study gains further insight into the novel role of Fbxo3 in BMP signaling. (C) 2015 Elsevier Inc. All rights reserved.