The atypical PKCs in inflammation: NF-κB and beyond

From the very early days of nuclear factor-?B (NF-?B) research, it was recognized that different protein kinase C (PKC) isoforms might be involved in the activation of NF-?B. Pharmacological tools and pseudosubstrate inhibitors suggested that these kinases play a role in this important inflammatory and survival pathway; however, it was the analysis of several genetic mouse knockout models that revealed the complexity and interrelations between the different components of the PB1 network in several cellular functions, including T-cell biology, bone homeostasis, inflammation associated with the metabolic syndrome, and cancer. These studies unveiled, for example, the critical role of PKC? as a positive regulator of NF-?B through the regulation of RelA but also its inflammatory suppressor activities through the regulation of the interleukin-4 signaling cascade. This observation is of relevance in T cells, where p62, PKC?, PKC?/?, and NBR1 establish a mesh of interactions that culminate in the regulation of T-cell effector responses through the modulation of T-cell polarity. Many questions remain to be answered, not just from the point of view of the implication for NF-?B activation but also with regard to the in vivo interplay between these pathways in pathophysiological processes like obesity and cancer.