Atypical protein kinase C isoforms differentially regulate directional keratinocyte migration during wound healing

Background: The epidermis possesses regenerative properties that become apparent only after wounding. Atypical protein kinase C (aPKC) isoforms aPKC zeta and aPKC lambda form a ternary complex with Par3 and Par6, and play crucial roles in establishing and maintaining epithelial cell polarity. The epidermal loss of aPKC lambda results in progressive depletion of hair follicle stem cells. However, it is unclear whether aPKCs have equivalent activities in epidermal regeneration. Objectives: To clarify functional differences between aPKC zeta and aPKC lambda in cutaneous wound healing. Methods: We compared cutaneous wound healing processes in vivo using mutant mice with genetic deletion of each aPKC isoform. We also analyzed functional differences between aPKC zeta and aPKC lambda in cell proliferation, directional cell migration, and formation of microtubules in vitro using primary keratinocytes established from each mutant mouse. Results: Wound healing was significantly retarded in epidermis-specific aPKC lambda knockout mice. In aPKC lambda deleted keratinocytes, the correct orientation of cell protrusions toward the wound was disrupted through the destabilization of Par6 beta. The elongation of stabilized beta-tubulin was also deteriorated in aPKC lambda-deleted keratinocytes, leading to defects in cell spreading. Conversely, wound healing and directional cell migration in aPKC zeta-deleted mice were comparable to those in their control littermates. Conclusions: aPKCs are not functionally equivalent; aPKC lambda, but not aPKC zeta, plays a primary role in cutaneous wound healing. (C) 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.