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Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks
Christina Schoenherr1, Adam Byron1, Emma Sandilands1
1Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Abstract:
Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described 'spatial rheostat' controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion. However, when Ambra1 cannot bind to FAK, abnormally high levels of phospho-Src and phospho-FAK accumulate at focal adhesions, positively regulating adhesion and invasive migration. Spatial control of active Src requires the trafficking proteins Dynactin one and IFITM3, which we identified as Ambra1 binding partners by interaction proteomics. We conclude that Ambra1 is a core component of an intracellular trafficking network linked to tight spatial control of active Src and FAK levels, and so crucially regulates their cancer-associated biological outputs.
Insights
The autophagy protein Ambra1 acts as a spatial rheostat, controlling cancer cell invasion by regulating the Src/FAK pathway. It targets active phospho-Src, influencing cell adhesion and migration.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Oncology
Background:
- The Src/FAK pathway is crucial for cancer cell migration and invasion.
- Autophagy proteins, like Ambra1, play roles in cellular stress responses.
- Dysregulation of focal adhesion dynamics contributes to cancer progression.
Purpose of the Study:
- To investigate a novel function of the autophagy protein Ambra1 in regulating the Src/FAK pathway.
- To elucidate the role of Ambra1 in controlling cancer cell adhesion, invasion, and migration.
- To identify Ambra1-interacting proteins involved in spatial regulation of signaling pathways.
Main Methods:
- Utilized mouse squamous cell carcinoma cells.
- Performed interaction proteomics to identify Ambra1 binding partners.
- Investigated the localization and regulation of Src and FAK proteins in relation to Ambra1.
Main Results:
- Identified Ambra1 as a 'spatial rheostat' for the Src/FAK pathway.
- Demonstrated Ambra1 regulates the targeting of active phospho-Src away from focal adhesions.
- Showed Ambra1 binding to FAK promotes directional sensing and invasion, while its absence leads to increased adhesion and migration.
Conclusions:
- Ambra1 is essential for the spatial control of active Src and FAK levels at focal adhesions.
- Ambra1 functions within an intracellular trafficking network involving Dynactin one and IFITM3.
- Ambra1 critically regulates cancer-associated biological outputs of the Src/FAK pathway.