Investigation of E3 ubiquitin ligase Smurf2 in the regulation of p38MAPK-mediated chemoresistance

p38 MAPK signaling pathway has been shown to mediate cellular responses to various stimuli including DNA damage. Research progress has attracted much attention on p38 MAPKs, as a promising drug target for cancer therapy. An increasingly appreciated route in p38MAPK regulation is through the interplay with the protein ubiquitination system (PUS), which controls a wide array of cellular functions through proteome regulation. As a crucial player in PUS enzymatic cascade, E3 ubiquitin ligases define the spatiotemporal nature of ubiquitination and confer specificity to this cascade. In this study, we investigated the regulatory role of E3 ubiquitin ligase, Smurf2, in p38MAPK-mediated chemoresistance. We found that Smurf2 directly binds and ubiquitinates p38MAPK in vivo and in vitro. Moreover, Smurf2 regulation of p38MAPK was further demonstrated in Smurf2 depleted cells, showing more intense and prolonged activation of p38MAPK upon DNA damage. Finally, in Smurf2-deficient cells we demonstrated alternations in cell resistance to genotoxic drugs, which was significantly compromised by p38MAPK inhibition. Altogether, our data establish a novel functional link between Smurf2, p38MAPK signaling cascade and chemosenstivity, and provide important insight into the role of Smurf2-p38MAPK axis in cancer.