title: Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks.
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.
authors.affiliation: Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Christina
authors.identifier: 0000-0002-0983-6168
authors.initials: C
authors.lastname: Schoenherr
authors.affiliation: Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Adam
authors.identifier: 0000-0002-5939-9883
authors.initials: A
authors.lastname: Byron
authors.affiliation: Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Sandilands
authors.affiliation: Centre for Nephrology, Division of Medicine, Royal Free Hospital Campus, London, United Kingdom.
authors.forename: Ketevan
authors.initials: K
authors.lastname: Paliashvili
authors.affiliation: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom.|College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.affiliation: System Biology Ireland, University College Dublin, Dublin, Ireland.
authors.forename: Amaya
authors.initials: A
authors.lastname: Garcia-Munoz
authors.affiliation: Department of Biology, University of Tor Vergata, Via della Ricerca Scientifica, Rome, Italy.|Cell Stress and Survival Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Cristina
authors.initials: C
authors.lastname: Valacca
authors.affiliation: Department of Biology, University of Tor Vergata, Via della Ricerca Scientifica, Rome, Italy.|Cell Stress and Survival Group, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Pediatric Hematology and Oncology, IRCSS Bambino Gesu Children's Hospital, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.affiliation: Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Margaret C
authors.identifier: 0000-0001-5882-1942
authors.initials: MC
authors.lastname: Frame
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D000072159:Dynactin Complex / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C521754:Ambra1 protein, mouse; D000072159:Dynactin Complex; D008565:Membrane Proteins; C462181:fragilis protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases
keywords: Ambra1; FAK; IFITM3; Src; cancer biology; cell biology; invasion; mouse; trafficking