PKA/Smurf1 signaling-mediated stabilization of Nur77 is required for anticancer drug cisplatin-induced apoptosis

The orphan nuclear receptor Nur77 regulates diverse cellular activities, including cell proliferation, differentiation and apoptosis. The c-Jun N-terminal kinase (JNK) have a dual role in controlling the function of Nur77. While JNK-mediated phosphorylation of Nur77 positively regulates its translocation to the mitochondria to induce apoptosis, it negatively regulates the stability of Nur77. The underlying mechanism for the dual role of JNK in regulating Nur77, however, is unclear. Here, we report that E3 ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) prevents Nur77 degradation through mediating its unconventional ubiquitination, thereby mitigating the JNK-mediated downregulating effect, which leads to Nur77 accumulation and subsequent translocation to mitochondria to trigger apoptosis. In this process, protein kinase A (PKA)-mediated phosphorylation of Smurf1 at Thr306 is a prerequisite step. Accordingly, cyclic AMP/PKA signaling switches the fate of Nur77 from degradation to triggering apoptosis in chemotherapy drug cisplatin-treated cells. Hence, our study revealed a novel mechanism, by which PKA/Smurf1 antagonizes the downregulating effect of JNK on Nur77, leading to the accumulation of Nur77 for apoptosis induction triggered by cisplatin.