Regulation of transforming growth factor beta signaling by ubiquitin-specific proteases in breast cancer. Ubiquitin-specific proteases (USPs) overexpressed and implicated in breast cancer regulate transforming growth factor beta (TGFβ) signaling at different levels in the signaling cascade. USP15, USP11 and USP4 inhibit TGFβ type I receptor degradation by preventing proteasomal destruction through deubiquitination and stabilization of TGFβ type I receptor, resulting in enhancement of TGFβ signaling. USP11 directly binds to the type I receptor whereas USP15 binds the receptor through complex formation with Smad7–Smurf2. USP4 also binds directly to the type I receptor but only when phosphorylated by AKT kinase. USP4 is phosphorylated in the nucleus by AKT kinase. Phosphorylated USP4 translocates to the membrane, binds and stabilizes type I receptor. TGFβ signaling can also be regulated at the coreceptor Smad level by USP9X. Smad4 mono-ubiquitination at K519 inhibits its binding with phospho-Smad2 and thus inhibits Smad 4 and TGFβ signaling. Through its deubiquitinating activity, US9X reverses mono-ubiquitination and stabilizes Smad4, resulting in the sustained activation of TGFβ signaling. P, phosphorylation; TF, transcription factor; Ub, ubiquitin.