When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Smad ubiquitylation regulatory factor-1 (Smurf1; EC 6.3.2.19) has been identified as a HECT type E3, and has been related to multiple biological processes such as cell growth and migration, and explored for several physiological functions in bone formation, embryonic development, and tumorigenesis. Smurf1 was identified as a negative regulator of BMP signaling, as it ubiquitinates Smad1 and Smad5 for proteasomal degradation to prevent the mild BMP signal from bursting into an overwhelming consequence. CDK8-mediated phosphorylation of Smad1/5 facilitates the transcriptional complex in activating its target genes. Furthermore, it promotes GSK3-mediated phosphorylation of Smad1/5, which leads to the capture of Smad1/5 by Smurf1.