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

• Loss of PDK1 impairs epidermal ACD, differentiation, and stratification
• PIP3-PDK1 signaling occurs preferentially at the apical side of dividing basal cells
• PDK1 is crucial for activation and recruitment of the apical complex in basal cells
• Restoration of Notch rescues the defective differentiation of keratinocytes in vitro

SummaryAsymmetric 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.

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