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A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human
Ajay Mishra1,2, Bénédicte Oulès1, Angela Oliveira Pisco1
1Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom.
Elife
|October 19, 2017
Summary
Protein phosphatases control skin cell commitment. A dynamic phosphatase network regulates epidermal homeostasis by managing the switch between stem cell renewal and differentiation, ensuring proper skin cell balance.
Area of Science:
- Cell biology
- Biochemistry
- Dermatology
Background:
- Epidermal homeostasis relies on a balance between stem cell renewal and terminal differentiation.
- The cellular commitment process, transitioning between these states, is not well understood.
- Understanding commitment is crucial for deciphering mechanisms of skin homeostasis.
Purpose of the Study:
- To characterize the molecular mechanisms underlying keratinocyte commitment.
- To identify key regulators of the transition from stem cell renewal to terminal differentiation.
- To elucidate the role of protein phosphatases in epidermal homeostasis.
Main Methods:
- Integration of transcriptomic and proteomic data from human keratinocytes.
- Induction of differentiation by cell detachment in suspension culture.
- Analysis of protein phosphatase networks and their interactions.
- Boolean network modeling to simulate cell state transitions.
Main Results:
- Cell detachment induces specific protein phosphatases (DUSP6, PPTC7, PTPN1, PTPN13, PPP3CA) that promote differentiation.
- These phosphatases negatively regulate ERK MAPK and positively regulate AP1 transcription factors.
- DUSP10 antagonizes commitment, while DUSP6 predominates at the commitment stage.
- A dynamic phosphatase network with transient interactions was identified.
- Boolean modeling revealed a switch between stable stem and differentiated states via an unstable committed state.
- Phosphatase expression shows spatial regulation in vivo and in vitro.
Conclusions:
- An auto-regulatory protein phosphatase network controls epidermal homeostasis.
- This network precisely regulates the onset and duration of the commitment process.
- Understanding phosphatase networks offers insights into maintaining skin health and treating related disorders.