Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner

• Published in: The Journal of biological chemistry 2013-05, Vol.288 (20), p.14158-14169
• Main Authors: Padmanabhan, Achuth, Li, Xiang, Bieberich, Charles J.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cancer Biology; Catalytic Domain; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Cyclic AMP-Dependent Protein Kinases - metabolism; Gene Expression Regulation, Enzymologic; Humans; Molecular Sequence Data; MYC; Phosphorylation; Polo-Like Kinase 1; Polo-like Kinase 1 (PLK1); Post-translational Modification; Proteasome Endopeptidase Complex - metabolism; Protein Isoforms - metabolism; Protein Kinase A (PKA); Protein Serine-Threonine Kinases - metabolism; Protein Synthesis and Degradation; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-myc - metabolism; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.432377

MYC levels are tightly regulated in cells, and deregulation is associated with many cancers. In this report, we describe the existence of a MYC-protein kinase A (PKA)-polo-like kinase 1 (PLK1) signaling loop in cells. We report that sequential MYC phosphorylation by PKA and PLK1 protects MYC from proteasome-mediated degradation. Interestingly, short term pan-PKA inhibition diminishes MYC level, whereas prolonged PKA catalytic subunit α (PKACα) knockdown, but not PKA catalytic subunit β (PKACβ) knockdown, increases MYC. We show that the short term effect of pan-PKA inhibition on MYC is post-translational and the PKACα-specific long term effect on MYC is transcriptional. These data also reveal distinct functional roles among PKA catalytic isoforms in MYC regulation. We attribute this effect to differential phosphorylation selectivity among PKA catalytic subunits, which we demonstrate for multiple substrates. Further, we also show that MYC up-regulates PKACβ, transcriptionally forming a proximate positive feedback loop. These results establish PKA as a regulator of MYC and highlight the distinct biological roles of the different PKA catalytic subunits. Background: MYC is rapidly degraded in cells, and its accumulation is associated with many human malignancies. Results: Sequential phosphorylation of MYC by protein kinase A (PKA) and polo-like kinase 1 (PLK1) protects MYC from proteasome-mediated degradation. Conclusion: A MYC-PKA-PLK1 signaling loop exists in cells. Significance: We highlight the importance of considering possible regulatory feedback loops while targeting molecules occupying hub positions in signaling pathways.