Negative regulation of RelA phosphorylation: Emerging players and their roles in cancer

• Regulation of RelA dephosphorylation is important for restraining RelA activity.
• Two families of phosphatases have been identified as direct RelA phosphatases.
• The tumor suppressor, LZAP, is associated with dephosphorylation of RelA and regulating PPM family members.
• Proteins that accelerate RelA dephosphorylation display tumor suppressor-like activities.

NF-κB signaling contributes to human disease processes, notably inflammatory diseases and cancer. Many advances have been made in understanding mechanisms responsible for abnormal NF-κB activation with RelA post-translational modification, particularly phosphorylation, proven to be critical for RelA function. While the majority of studies have focused on identifying kinases responsible for NF-κB phosphorylation and pathway activation, recently progress has also been made in understanding the negative regulators important for restraining RelA activity. Here we summarize negative regulators of RelA phosphorylation, their targeting sites in RelA and biological functions through negative regulation of RelA activation. Finally, we emphasize the tumor suppressor-like roles that these negative regulators can assume in human cancers.