期刊
CELL REPORTS
卷 15, 期 8, 页码 1615-1623出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.04.051
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资金
- SDRC Pilot & Feasibility Studies Program [P30AR44535]
- Uehara Memorial Foundation Research Fellowship
- Japanese Society for Investigative Dermatology (JSID)'s Fellowship SHISEIDO Award
- Japan Society for the Promotion of Science (JSPS) KAKENHI [26670529]
- NIH [R37-AI33443]
- Grants-in-Aid for Scientific Research [15H05790, 26670529] Funding Source: KAKEN
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. PDK1(CKO) keratinocytes do not undergo calcium-induced activation of aPKC or IGF1-induced activation of AKT and fail to differentiate. PDK1(CKO) 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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