Erk1/2 Inactivation-Induced c-Jun Degradation Is Regulated by Protein Phosphatases, UBE2d3, and the C-Terminus of c-Jun

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 3889
• Main Authors: Ouyang, Weiming, Frucht, David M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.04.2021; MDPI
• Subjects: Animals; c-Jun; c-Jun protein; C-Terminus; Cell Line, Tumor; COP1; Degradation; Enzyme Activation; Enzymes; Extracellular signal-regulated kinase; Gene expression; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Jun protein; Kinases; Mammals; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Biological; Phosphatase; Phosphoprotein phosphatase; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Protein Binding; protein degradation; Protein phosphatase; Proteins; Proteolysis; Transcription factors; UBE2d3; Ubiquitin; ubiquitin E3 ligase; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-protein ligase; c-Jun; COP1; protein degradation; protein phosphatase; UBE2d3; ubiquitin E3 ligase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22083889

Constitutive photomorphogenic 1 (COP1) is the ubiquitin E3 ligase that mediates degradation of c-Jun protein upon Erk1/2 inactivation. It remains unknown how this protein degradation pathway is regulated. In this study, we investigated the roles of protein phosphatases, ubiquitin-conjugating E2 enzymes (UBE2), and an intrinsic motif of c-Jun in regulating this degradation pathway. By using pharmacological inhibitors and/or gene knockdown techniques, we identified protein phosphatase 1 (PP1) and PP2A as the phosphatases and UBE23d as the UBE2 promoting c-Jun degradation, triggered by Erk1/2 inactivation. In addition, we report that the C-terminus of c-Jun protein facilitates its degradation. The addition of a C-terminal tag or deletion of the last four amino acid residues from the C-terminus of c-Jun protects it from degradation under Erk1/2-inactivating conditions. Taken together, this study reveals that the Erk1/2 inactivation-triggered and COP1-mediated c-Jun degradation is extrinsically and intrinsically regulated, providing a new understanding of the mechanisms underlying this protein degradation pathway.