NOTCH4 intracellular domain fragment (NICD4) binds phosphorylated SMAD3 upon activation of TGF-beta signaling. (Sun et al. 2005, Grabias and Konstantopoulos 2013). NICD4 may also bind SMAD2 and SMAD4 (Sun et al. 2005). NICD4 promotes ubiquitination and proteasome-mediated degradation of SMAD3 through and unknown mechanism (Grabias and Konstantopoulos 2013) and inhibits transcription mediated by the heterotrimer of SMAD3, SMAD2 and SMAD4, thus negatively regulating TGF-beta signaling (Sun et al. 2005, Grabias and Konstantopoulos 2013).