PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division.
PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division.
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DOI：
10.1016/j.celrep.2016.04.051
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发表时间：
2016-05-24
期刊：
影响因子：
8.8
通讯作者：
Ghosh S
中科院分区：
文献类型：
--
作者：
Dainichi T;Hayden MS;Park SG;Oh H;Seeley JJ;Grinberg-Bleyer Y;Beck KM;Miyachi Y;Kabashima K;Hashimoto T;Ghosh S
垂直方向的不对称细胞分裂（ACD）促进细胞分化并形成成层上皮。然而，调控ACD的上游信号尚未被确定。在这里，我们报道了磷酸肌苷依赖性激酶1 （PDK1）在上皮细胞ACD的建立中起关键作用。磷脂酰肌醇三磷酸（PIP3）的产生局限于基底细胞的顶端。非典型蛋白激酶C （aPKC）的不对称募集和分配缺陷（PAR） 3在PDK1条件敲除（CKO）表皮中受损。PDK1CKO角质形成细胞不经历钙诱导的aPKC激活或igf1诱导的AKT激活，无法分化。PDK1CKO表皮显示Notch （ACD的下游效应物）的表达降低，Notch的修复可以在体外修复分化诱导的Notch靶点的缺陷表达。因此，我们提出PDK1信号通过作为ACD和notch依赖性分化程序的激活者和组织者来调节发育中的表皮中基底到上基底的开关。
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 phosphatidylinositol triphosphate (PIP3) is localized to the apical side of basal cells. Asymmetric recruitment of atypical protein kinase C (aPKC), and partitioning defective (PAR) 3, are 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.