Beta 1-integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes

Rachel Barrow-McGee, Naoki Kishi, Carine Joffre, Ludovic Ménard, Alexia Hervieu, Bakhouche A. Bakhouche, Alejandro J. Noval, Anja Mai, Camilo Guzmán, Luisa Robbez-Masson, Xavier Iturrioz, James Hulit, Caroline H. Brennan, Ian R. Hart, Peter J. Parker, Johanna Ivaska and Stéphanie Kermorgant ()
Additional contact information
Rachel Barrow-McGee: 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
Naoki Kishi: 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
Carine Joffre: 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
Ludovic Ménard: 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
Alexia Hervieu: 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
Bakhouche A. Bakhouche: 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
Alejandro J. Noval: 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
Anja Mai: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland
Camilo Guzmán: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland
Luisa Robbez-Masson: 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
Xavier Iturrioz: Protein Phosphorylation Laboratory, Francis Crick Institute
James Hulit: 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
Caroline H. Brennan: School of Biological and Chemical Sciences, Queen Mary University of London
Ian R. Hart: 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
Peter J. Parker: Protein Phosphorylation Laboratory, Francis Crick Institute
Johanna Ivaska: University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland
Stéphanie Kermorgant: 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

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11942

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