A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
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DOI：
10.1101/125765
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发表时间：
2017-03
期刊：
影响因子：
7.7
通讯作者：
Ajay Mishra;A. Pisco;Bénédicte Oulès;T. Ly;Kifayathullah Liakath-Ali;G. Walko;Priyalakshmi Viswanathan;Jagdeesh Nijjhar;Sara-Jane Dunn;A. Lamond;F. Watt
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文献类型：
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作者：
Ajay Mishra;A. Pisco;Bénédicte Oulès;T. Ly;Kifayathullah Liakath-Ali;G. Walko;Priyalakshmi Viswanathan;Jagdeesh Nijjhar;Sara-Jane Dunn;A. Lamond;F. Watt
表皮稳态取决于干细胞更新和终末分化之间的平衡。两种细胞状态之间的转变（称为承诺）人们知之甚少。在这里，我们通过整合来自分散的原代人角质形成细胞的转录组学和蛋白质组学数据来表征承诺，所述原代角质形成细胞悬浮长达12小时以诱导分化。我们发现细胞脱离会诱导蛋白磷酸酶网络。前定型磷酸酶（包括 DUSP6、PPTC7、PTPN1、PTPN13 和 PPP3CA）通过负向调节 ERK MAPK 和正向调节 AP1 转录因子来促进分化。它们的活性被伴随的 DUSP10 上调所拮抗。磷酸酶相互作用的布尔网络模型将承诺确定为干细胞和分化细胞状态之间本质上不稳定的生物转换。此外，磷酸酶表达在体内和体外均受到空间调节。我们得出的结论是，自动调节磷酸酶网络通过控制承诺的开始和持续时间来维持表皮稳态。
Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension for up to 12h to induce differentiation. We find that cell detachment induces a network of protein phosphatases. The pro-commitment phosphatases – including DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Their activity is antagonised by concomitant upregulation of DUSP10. Boolean network modelling of phosphatase interactions identifies commitment as an inherently unstable biological switch between the stem and differentiated cell states. Furthermore, phosphatase expression is spatially regulated both in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.