nPKCs

nPKCs, or novel protein kinase C enzymes, are a subfamily of the protein kinase C (PKC) family. Members of this group include PKCδ, PKCε, PKCη, and PKCθ. Like other PKCs, they are serine/threonine kinases that participate in signaling networks controlling diverse cellular processes, but they differ from classical PKCs in their calcium requirements.

Activation of nPKCs is primarily mediated by diacylglycerol (DAG) and lipid cofactors rather than calcium. The regulatory region contains a C1 domain that binds DAG and phorbol esters, enabling membrane association and activation. Unlike classical PKCs, nPKCs are largely calcium-independent, though they can be regulated by other lipid and protein interactions. Activation is commonly downstream of receptor signaling that engages phospholipase C to generate DAG, such as GPCRs and receptor tyrosine kinases.

Regulation involves multiple phosphorylation events that support maturation and stability. After initial synthesis, PKCs are phosphorylated at conserved motifs by kinases such as PDK1, enabling proper folding and activity. Subcellular localization of nPKCs shifts from the cytosol to membrane compartments and other organelles upon activation, influencing substrate accessibility and signaling outcomes. Isoform-specific regulation and localization contribute to distinct biological roles.

Biological roles of nPKCs are diverse and context dependent. They participate in signaling pathways governing cell growth, differentiation, survival and apoptosis, immune cell function, and metabolic regulation. PKCθ is particularly important in T-cell receptor signaling, while PKCδ and PKCε have widely varying roles in proliferation and cell death. Dysregulation of nPKCs has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making them a subject of ongoing research and therapeutic interest.