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Published on: September 13, 2018
The Hippo-YAP signaling pathway and contact inhibition of growth
Barry M Gumbiner1, Nam-Gyun Kim
1Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Abstract:
The Hippo-YAP pathway mediates the control of cell proliferation by contact inhibition as well as other attributes of the physical state of cells in tissues. Several mechanisms sense the spatial and physical organization of cells, and function through distinct upstream modules to stimulate Hippo-YAP signaling: adherens junction or cadherin-catenin complexes, epithelial polarity and tight junction complexes, the FAT-Dachsous morphogen pathway, as well as cell shape, actomyosin or mechanotransduction. Soluble extracellular factors also regulate Hippo pathway signaling, often inhibiting its activity. Indeed, the Hippo pathway mediates a reciprocal relationship between contact inhibition and mitogenic signaling. As a result, cells at the edges of a colony, a wound in a tissue or a tumor are more sensitive to ambient levels of growth factors and more likely to proliferate, migrate or differentiate through a YAP and/or TAZ-dependent process. Thus, the Hippo-YAP pathway senses and responds to the physical organization of cells in tissues and coordinates these physical cues with classic growth-factor-mediated signaling pathways. This Commentary is focused on the biological significance of Hippo-YAP signaling and how upstream regulatory modules of the pathway interact to produce biological outcomes.
Insights
The Hippo-YAP pathway controls cell proliferation using physical cues like contact inhibition. It integrates tissue organization signals with growth factors, influencing cell behavior at tissue boundaries.
Area of Science:
- Cell biology
- Developmental biology
- Biophysics
Background:
- The Hippo-YAP pathway is a critical regulator of cell proliferation, acting downstream of cell density and tissue architecture.
- Physical cues, including cell-cell adhesion, polarity, and mechanical forces, are increasingly recognized as key regulators of this pathway.
- Understanding how these physical signals are integrated with soluble factors is essential for comprehending tissue homeostasis and disease.
Purpose of the Study:
- To review the biological significance of the Hippo-YAP signaling pathway.
- To elucidate the mechanisms by which upstream regulatory modules sense cellular physical states.
- To explain how these physical cues are integrated with growth factor signaling to control cell proliferation, migration, and differentiation.
Main Methods:
- This commentary synthesizes existing research on the Hippo-YAP pathway.
- It focuses on the upstream regulators that sense cell physical properties and their integration with signaling pathways.
- Literature review and conceptual analysis of Hippo-YAP pathway regulation.
Main Results:
- The Hippo-YAP pathway integrates diverse physical cues, including cell-cell junctions, polarity, cell shape, and mechanical forces (mechanotransduction).
- These physical inputs converge to modulate the activity of the core Hippo kinase complex and its downstream effectors, YAP and TAZ.
- The pathway exhibits a reciprocal relationship with mitogenic signaling, where physical cues can sensitize cells to growth factors, particularly at tissue edges.
Conclusions:
- The Hippo-YAP pathway acts as a central sensor of tissue organization, translating physical information into cellular responses.
- It coordinates cell proliferation, migration, and differentiation by integrating contact inhibition signals with extracellular growth factors.
- Dysregulation of Hippo-YAP signaling due to altered physical cues is implicated in developmental processes and diseases like cancer.
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