Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks

Schoenherr, C., Byron, A., Sandilands, E., Paliashvili, K., Baillie, G. S. , Valacca, C., Cecconi, F., Serrels, B. and Frame, M. C. (2017) Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks. eLife, 6, e23172. (doi: 10.7554/eLife.23172) (PMID:28362576)

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.

• Item Type: Articles
• Additional Information: This work was funded by CR-UK Programme Grant (C157/A15703) and European Research Council Advanced Investigator Grant (294440 Cancer Innovation) to M Frame.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baillie, Professor George and Frame, Mrs Margaret and Sandilands, Dr Emma and Serrels, Dr Bryan
• Authors: Schoenherr, C., Byron, A., Sandilands, E., Paliashvili, K., Baillie, G. S., Valacca, C., Cecconi, F., Serrels, B., and Frame, M. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: eLife
• Publisher: eLife Sciences Publications
• ISSN: 2050-084X
• ISSN (Online): 2050-084X
• Copyright Holders: Copyright © 2017 Schoenherr et al.
• First Published: First published in eLife 6:e23172
• Publisher Policy: Reproduced under a Creative Commons License