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Nat Commun. 2016 Jun 23;7:11942. doi: 10.1038/ncomms11942.

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

Author information

1
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.
2
University of Turku, Centre for Biotechnology and VTT Technical Research Centre of Finland, FI-20520 Turku, Finland.
3
Protein Phosphorylation Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
4
School of Biological and Chemical Sciences, Queen Mary University of London, 327 Mile End Road, London E1 4NS, UK.
5
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.
6
Division of Cancer Studies, King's College School of Medicine, St Thomas Street, London SE1 1UL, UK.
7
Department of Biochemistry and Food Chemistry, University of Turku, FI-20520 Turku, Finland.

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.

PMID:
27336951
PMCID:
PMC4931016
DOI:
10.1038/ncomms11942
[Indexed for MEDLINE]
Free PMC Article

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