RT Journal Article
SR Electronic
T1 A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 125765
DO 10.1101/125765
A1 Ajay Mishra
A1 Angela Oliveira Pisco
A1 Benedicte Oules
A1 Tony Ly
A1 Kifayathullah Liakath-Ali
A1 Gernot Walko
A1 Priyalakshmi Viswanathan
A1 Jagdeesh Nijjher
A1 Sara-Jane Dunn
A1 Angus I. Lamond
A1 Fiona M. Watt
YR 2017
UL http://biorxiv.org/content/early/2017/04/08/125765.abstract
AB 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.