A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

Ajay Mishra, Bénédicte Oulès, Angela Oliveira Pisco, Tony Ly, Kifayathullah Liakath-Ali, Gernot Walko, Priyalakshmi Viswanathan, Matthieu Tihy, Jagdeesh Nijjhar, Sara-Jane Dunn, Angus I. Lamond, Fiona M. Watt (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
243 Downloads (Pure)

Abstract

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 to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.
Original languageEnglish
Article numbere27356
Pages (from-to)1-20
Number of pages20
JournaleLife
Volume6
Early online date18 Oct 2017
DOIs
Publication statusPublished - 18 Oct 2017

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