title: Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.
abstract: Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis. Here we report that an integrin influences signalling of an RTK, c-Met, from inside the cell, to promote anchorage-independent cell survival. Thus, c-Met and β1-integrin co-internalize and become progressively recruited on LC3B-positive 'autophagy-related endomembranes' (ARE). In cells growing in suspension, β1-integrin promotes sustained c-Met-dependent ERK1/2 phosphorylation on ARE. This signalling is dependent on ATG5 and Beclin1 but not on ATG13, suggesting ARE belong to a non-canonical autophagy pathway. This β1-integrin-dependent c-Met-sustained signalling on ARE supports anchorage-independent cell survival and growth, tumorigenesis, invasion and lung colonization in vivo. RTK-integrin cooperation has been assumed to occur at the plasma membrane requiring integrin 'inside-out' or 'outside-in' signalling. Our results report a novel mode of integrin-RTK cooperation, which we term 'inside-in signalling'. Targeting integrin signalling in addition to adhesion may have relevance for cancer therapy.
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Barrow-McGee
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kishi
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Carine
authors.identifier: 0000-0002-7551-356X
authors.initials: C
authors.lastname: Joffre
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Ménard
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Alexia
authors.initials: A
authors.lastname: Hervieu
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Bakhouche A
authors.initials: BA
authors.lastname: Bakhouche
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Noval
authors.affiliation: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland, FI-20520 Turku, Finland.
authors.forename: Anja
authors.initials: A
authors.lastname: Mai
authors.affiliation: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland, FI-20520 Turku, Finland.
authors.forename: Camilo
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Luisa
authors.initials: L
authors.lastname: Robbez-Masson
authors.affiliation: Protein Phosphorylation Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Iturrioz
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Hulit
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, 327 Mile End Road, London E1 4NS, UK.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Brennan
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.affiliation: Protein Phosphorylation Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.|Division of Cancer Studies, King's College School of Medicine, St Thomas Street, London SE1 1UL, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
authors.affiliation: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland, FI-20520 Turku, Finland.|Department of Biochemistry and Food Chemistry, University of Turku, FI-20520 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.affiliation: Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kermorgant
mesh_terms: D000818:Animals; D001343:Autophagy; D063646:Carcinogenesis; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019012:Integrin beta1; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met