sorce data.xlsx

RNF214 is an understudied ubiquitin ligase without any knowledge of its biological functions orprotein substrates. Here we show that the TEAD transcription factorsin the Hippo pathway are substrates of RNF214. RNF214 inducesnon-proteolytic ubiquitylation at a conservedlysineresidueof TEADs,enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling.Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a new signaling axis of RNF214-TEAD-YAPand suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.