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 Nijjher,
Sara-Jane Dunn,
Angus I Lamond,
Fiona M Watt
Affiliations
Ajay Mishra
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom; Department of Chemical Engineering and Biotechnology, Cambridge Infinitus Research Centre, University of Cambridge, Cambridge, United Kingdom
Bénédicte Oulès
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Tony Ly
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, United Kingdom; Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
Kifayathullah Liakath-Ali
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Gernot Walko
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Priyalakshmi Viswanathan
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom; Laboratory of Cerebral Physiology, Université Paris Descartes, Paris, France
Jagdeesh Nijjher
Centre for Stem Cells and Regenerative Medicine, King’s College London, London, United Kingdom
Sara-Jane Dunn
Microsoft Research, Cambridge, United Kingdom; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
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.