aPKC

aPKC (atypical protein kinase C) refers to a subgroup of the protein kinase C (PKC) family that lacks the calcium‑ and diacylglycerol‑binding domains characteristic of conventional and novel PKCs. The atypical isoforms, primarily PKCζ (encoded by PRKCZ) and PKCι/λ (encoded by PRKCI), are activated primarily through protein–protein interactions and phosphoinositide binding rather than by second‑messenger lipids. Both isoforms possess an N‑terminal regulatory region containing a pseudosubstrate motif and a C‑terminal catalytic domain with conserved serine/threonine kinase activity.

Cell‑biological functions of aPKC are centered on the establishment and maintenance of cell polarity. In epithelial cells, aPKC forms part of the Par complex together with Par3 and Par6, where it phosphorylates substrates such as Lgl, Crumbs and atypical cadherins to segregate apical and basolateral membrane domains. Similar roles are observed in neuronal dendrite specification, asymmetric stem‑cell division, and directed cell migration. aPKC also participates in signaling pathways downstream of PI3K, NF‑κB and MAPK, acting as a scaffold that integrates extracellular cues with cytoskeletal remodeling.

Regulation of aPKC activity involves phosphorylation of the activation loop (Thr410 in PKCζ, Thr403 in PKCι) by phosphoinositide‑dependent kinase‑1, and inhibitory phosphorylation by PDK1 in certain contexts. Interaction with phosphatidylinositol‑3,4,5‑trisphosphate, the small GTPase Cdc42, and scaffolding proteins such as Par6 modulate its spatial activation.

Dysregulation of aPKC has been implicated in cancer, where overexpression or constitutive activation promotes oncogenic signaling, epithelial‑mesenchymal transition, and drug resistance. Mutations in PRKCI are associated with certain lung and ovarian carcinomas, and aberrant aPKC activity has been linked to neurodevelopmental disorders and neurodegeneration.

Because of its central role in polarity and signaling, aPKC remains a focus of pharmacological research, with small‑molecule inhibitors and peptide disruptors under investigation for therapeutic potential in oncology and neurobiology.