Role Of P120-catenin Mono-ubiquitination In Adherens Junction Disassembly During TGF?-induced EMT

Epithelial-mesenchymal transition(EMT),which is regulated transcriptionally and non-transcriptionally,has fundamental roles in physiological and pathological processes,such as embryonic development,wound healing,tumor metastasis and multiple fibrosis diseases.It's executed in response to various factors by inducing expression of mesenchymal transcription factors such as SNAI1/2,ZEB,TWIST1,and activating signaling cascades to break down cellular junctions,including tight junctions(TJs),adherens junctions(AJs),gap junctions,desmosomes and hemidesmosomes.Previous study shows that E3 ligase Smurfl targets RhoA for degradation at tight junction region during TGF?-induced EMT,leading to cortical actin dissolution and TJ dissociation.However,how AJs disassemble remains elusive.Herein,we discovered that TGF? signaling recruits Smurfl to adherens junctions to target p120-catenin for mono-ubiquitination,resulting in adherens junction dissociation.Inhibition of p120-catenin ubiquitination significantly blocks AJ dissolution,and consequent TJ dissociation,hence attenuates lung metastasis of murine breast cancer.Thereby,our study reveals a mechanism of TGF?-induced AJ disassembly and the sequential evens of cellular junction dissolution during TGF?-induced EMT.