Switching of the c-Myc protein degradation pathway depending on the PP2A-B55a complex levels

The transcription factor c-Myc is a key oncoprotein that regulates over 15% of all genes. Protein phosphatase 2A (PP2A), a crucial tumor suppressor, destabilizes c-Myc protein. Classically, dephosphorylation of Ser62 at c-Myc by PP2A and subsequent phosphorylation at Thr58 has been thought to promote c-Myc ubiquitination mediated by the E3 ligase F-box and WD repeat domain containing 7 (FBXW7). However, recent studies indicate that FBXW7 preferentially ubiquitinates c-Myc when both Thr58 and Ser62 are phosphorylated. This finding leaves the regulatory mechanism of c-Myc by PP2A unsolved. In this study, we demonstrate that a decrease in the PP2A-B55a complex leads to FBXW7-mediated c-Myc degradation through Thr58 phosphorylation, whereas an increase in the PP2A-B55a complex causes ubiquitin-protein ligase E3 component N-recognin 5 (UBR5)-mediated c-Myc degradation independent of c-Myc phosphorylation. We further demonstrated that the PP2A-B55a complex binds and dephosphorylates UBR5. In contrast, B55d, which belongs to the same B55 family and shares a common core structure, demonstrated a lower affinity for UBR5 and did not induce c-Myc degradation. Our findings provide new insights into the mechanism of c-Myc degradation and serve as a key to resolving the contradiction between PP2A activation and c-Myc degradation.