PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division

Abstract

Asymmetric cell division (ACD) in a perpendicular orientation promotes cell differentiation and organizes the stratified epithelium. However, the upstream cues regulating ACD have not been identified. Here, we report that phosphoinositide-dependent kinase 1 (PDK1) plays a critical role in establishing ACD in the epithelium. Production of phosphatidyl inositol triphosphate (PIP3) is localized to the apical side of basal cells. Asymmetric recruitment of atypical protein kinase C (aPKC) and partitioning defective (PAR) 3 is impaired in PDK1 conditional knockout (CKO) epidermis. PDK1CKO keratinocytes do not undergo calcium-induced activation of aPKC or IGF1-induced activation of AKT and fail to differentiate. PDK1CKO epidermis shows decreased expression of Notch, a downstream effector of ACD, and restoration of Notch rescues defective expression of differentiation-induced Notch targets in vitro. We therefore propose that PDK1 signaling regulates the basal-to-suprabasal switch in developing epidermis by acting as both an activator and organizer of ACD and the Notch-dependent differentiation program. Dainichi et al. demonstrate that PDK1 plays a critical role in asymmetric cell division, wherein PDK1 regulates the activation of AKT, as well as the activation and redistribution of aPKC. PDK1 signaling from the apical side of basal keratinocytes regulates the basal-to-suprabasal switch in epithelial stratification and the Notch-dependent differentiation program.