Fig. 1: Regulation of ER and TGF-β signalling by UCHL1.
From: UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology
a Regulation of ER by UCHL1 through the stabilisation of EGFR. EGFR homeostasis is maintained by Ub ligases and DUBs; however, overexpression of UCHL1 tips this balance towards deubiquitination and stabilisation of EGFR, and subsequent hyperactivation of MAPK signalling, thereby downregulating ERα expression and gene transcription. Targeting UCHL1 could promote proteasomal degradation of EGFR, and thus influence ER expression and responses to anti-estrogen therapy [41]. b Regulation of TGF-β signalling by UCHL1. UCHL1 is proposed to regulate TGF-β signaling in metastatic breast cancer by deubiquitinating and stabilising TGFβR1 and SMAD2/3 in TNBC and aggressive tumours. TGF-β signalling is induced by TGF-β binding to TGFβR2, which subsequently phosphorylates TGFβR1 which in turn phosphorylates Smad2/3. Phosphorylated Smad2/3 binds Smad4 and the protein complex is translocated to the nucleus to regulate target gene transcription. Knockdown or inhibition of UCHL1 has been proposed to exert anticancer effects by rescuing the ubiquitination and degradation of TGFβR1 and SMAD2/3 [54].
