aPKCs

Atypical protein kinase C (aPKC) refers to a subgroup of the protein kinase C (PKC) family characterized by insensitivity to calcium and diacylglycerol (DAG) and by regulation primarily through protein–protein interactions rather than second messengers. In humans, the two main isoforms are PKC-ζ (zeta) and PKC-ι (iota); in rodents and some literature, PKC-λ (lambda) is treated as the functional ortholog of PKC-ι. They share a catalytic kinase domain and a regulatory region that contains a PB1 (Phox and Bem1) domain, which mediates interactions with other PB1-containing proteins such as Par-3 and Par-6 to form complexes that influence localization and activity.

Activation and regulation of aPKCs rely on assembly into protein complexes and phosphorylation by upstream kinases, notably PDK1, at their activation loop. Unlike classical and novel PKCs, aPKCs do not respond directly to Ca2+ or DAG; instead, their activity is controlled through scaffolding interactions that position them at sites such as cell–cell junctions and areas of cell polarity. The PB1-mediated interactions help recruit aPKCs to polarity complexes and signaling hubs, linking them to broader cellular programs.

Functions of aPKCs are diverse but interconnected. They play key roles in establishing and maintaining cell polarity, particularly in epithelia, through regulation of tight junctions and apical–basal organization. They participate in signal transduction pathways including PI3K/Akt and NF-κB signaling, and they influence metabolism, immune responses, and development. Aberrant aPKC signaling has been associated with cancer progression, metabolic disorders, and neurodegenerative diseases, making them a focus of research and potential therapeutic targeting.