TY - JOUR T1 - A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis JF - bioRxiv DO - 10.1101/125765 SP - 125765 AU - Ajay Mishra AU - Angela Oliveira Pisco AU - Benedicte Oules AU - Tony Ly AU - Kifayathullah Liakath-Ali AU - Gernot Walko AU - Priyalakshmi Viswanathan AU - Jagdeesh Nijjher AU - Sara-Jane Dunn AU - Angus I. Lamond AU - Fiona M. Watt Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/08/125765.abstract N2 - 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. ER -