title: 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. 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.
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Dainichi
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA; Department of Dermatology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hayden
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Sung-Gyoo
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Seeley
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.
authors.forename: Yenkel
authors.initials: Y
authors.lastname: Grinberg-Bleyer
authors.affiliation: Department of Dermatology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Beck
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miyachi
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Kurume University Institute of Cutaneous Cell Biology, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Microbiology & Immunology, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA. Electronic address: sg2715@columbia.edu.
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D000818:Animals; D060049:Asymmetric Cell Division; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D010641:Phenotype; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010716:Phosphatidylinositols; D051880:Receptors, Notch; C483312:phosphoinositide 3-phosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C115015:PKC-3 protein; D011493:Protein Kinase C; D002118:Calcium