Understanding the dynamics of hippo pathway signaling
Abstract/Contents
- Abstract
- Yes-associated protein 1 (YAP) is a transcriptional co-activator in the Hippo pathway, playing critical roles in mechano-transduction, organ size control, and regeneration. Here, we report a robust experimental platform for real-time visualization of native YAP dynamics and downstream gene expression. Using this platform, we show that activation of YAP target genes is preceded by localization resets, which are dramatic, concerted departure/re-entry cycles of nuclear YAP. These resets could be induced by intracellular calcium release, modulation of Src-kinase activity, and mitosis. Using nascent-transcription reporter knockins, we found that native YAP target-gene activation is strictly correlated to such localization resets. Oncogenically transformed cells, with chronically elevated YAP-driven transcription, lacked these resets, but displayed rapid nucleo-cytoplasmic exchange of YAP, suggesting an escape from compartmentalization-based control. Measurement of chromatin binding kinetics revealed no detectable binding of YAP in Ras-transformed cell lines. However, untransformed cells showed a high degree of bulk YAP-chromatin binding. Taken together, we propose that YAP activity is not a simple linear function of nuclear enrichment. We suggest a novel mode of transcriptional regulation involving the dynamic re-partitioning of YAP prior to gene activation, where high nuclear retention of YAP through non-specific binding acts to gate transcription activity. Under oncogenic signaling contexts, this gating mechanism is by-passed, and rapid nucleo-cytoplasmic communication of YAP aids unregulated transcription.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Franklin, John Matthew | |
|---|---|---|
| Degree supervisor | Liphardt, Jan | |
| Degree supervisor | Spakowitz, Andrew James | |
| Thesis advisor | Liphardt, Jan | |
| Thesis advisor | Spakowitz, Andrew James | |
| Thesis advisor | Dunn, Alexander Robert | |
| Degree committee member | Dunn, Alexander Robert | |
| Associated with | Stanford University, Department of Chemical Engineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | John Matthew Franklin. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by John Matthew Franklin
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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