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Updated: Jun 13, 2025
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Generation and Culturing of Primary Human Keratinocytes from Adult Skin
Published on: December 22, 2017
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A feedback loop between plakophilin 4 and YAP signaling regulates keratinocyte differentiation
Lisa Müller1,2, Tony Gutschner2, Mechthild Hatzfeld1
1Institute of Molecular Medicine, Section for Pathochemistry, Martin Luther University Halle-Wittenberg, Charles Tanford Protein Research Center, Kurt-Mothes-Str. 3A, 06120 Halle, Germany.
Iscience
|September 17, 2024
Summary
Plakophilin 4 (PKP4) regulates skin cell growth and differentiation by interacting with the Hippo signaling pathway. PKP4 controls YAP/TAZ activity, impacting cell adhesion and proliferation.
Area of Science:
- Cell Biology
- Developmental Biology
- Cancer Biology
Background:
- The Hippo signaling pathway is crucial for organ size control and tissue homeostasis.
- Dysregulation of the Hippo pathway and its downstream effectors YAP/TAZ is implicated in cancer development.
- Adherens junctions are key regulators of YAP/TAZ activity.
Purpose of the Study:
- To investigate the role of Plakophilin 4 (PKP4) in regulating epidermal proliferation and differentiation.
- To elucidate the interaction between PKP4 and the Hippo signaling pathway components, including YAP/TAZ.
- To understand the feedback mechanisms controlling cell adhesion, proliferation, and differentiation.
Main Methods:
- Depletion of PKP4 using specific techniques.
- Analysis of cell proliferation and differentiation markers in epidermal cells.
- Immunoprecipitation and co-localization studies to assess protein interactions.
- Western blotting to evaluate protein levels and localization.
Main Results:
- PKP4 depletion led to increased proliferation and premature epidermal differentiation.
- PKP4 directly interacted with Hippo pathway components, including YAP/TAZ.
- PKP4 promoted nuclear YAP localization and target gene expression.
- In differentiated keratinocytes, PKP4 localized YAP to cell junctions, inhibiting its transcriptional activity.
- YAP depletion reduced PKP4 levels, suggesting a feedback loop.
Conclusions:
- PKP4 acts as a critical regulator of epidermal homeostasis by modulating the Hippo-YAP/TAZ signaling axis.
- PKP4 balances cell proliferation and differentiation through context-dependent regulation of YAP/TAZ.
- A feedback mechanism involving YAP and PKP4 controls keratinocyte adhesion, proliferation, and differentiation.
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