Mechanical strain induces E-cadherin dependent activation of Yap1 and ß-catenin to drive cell cycle re-entry
Abstract/Contents
- Abstract
- Mechanical strain regulates the development, organization and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. We showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle re-entry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin. Inhibition of Yap1- and β-catenin-mediated transcription blocked cell cycle re-entry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion and β-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Our results indicate that activation of Yap1 and β-catenin is a master regulator of mechanical strain-induced cell proliferation, and cadherins are signaling centers required for cellular responses to externally applied force. While both mechanical force and Wnt Signaling activate β-catenin-mediated transcription to promote proliferation, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate β-catenin signaling and cell division. We showed that mechanical strain induced Src-dependent phosphorylation of Y654 β-catenin and β-catenin accumulation, increasing β-catenin-mediated transcription. Under these conditions, however, cells accumulated in S/G2 but did not divide. Blocking β-catenin degradation through Casein Kinase I inhibition or Wnt3A addition increased β-catenin-mediated transcription and strain-induced accumulation of S/G2 cells. Significantly, only the combination of mechanical strain and Wnt/β-catenin activation triggered S/G2 cells to divide. These results indicate that strain-induced Src phosphorylation of β-catenin and Wnt-dependent β-catenin stabilization can synergize to increase β-catenin-mediated transcription to a level required for mitosis. Thus local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions and maintain tissue homeostasis.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Benham-Pyle, Blair Whitney | |
|---|---|---|
| Associated with | Stanford University, Cancer Biology Program. | |
| Primary advisor | Nelson, William | |
| Thesis advisor | Nelson, William | |
| Thesis advisor | Ferrell, James Ellsworth | |
| Thesis advisor | Nusse, Roel, 1950- | |
| Thesis advisor | Pruitt, Beth | |
| Thesis advisor | Weis, William I | |
| Advisor | Ferrell, James Ellsworth | |
| Advisor | Nusse, Roel, 1950- | |
| Advisor | Pruitt, Beth | |
| Advisor | Weis, William I |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Blair Whitney Benham-Pyle. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Blair Whitney Benham-Pyle
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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