Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.
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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.
AuthorsBarrow-McGee, R; Kishi, N; Joffre, C; Ménard, L; Hervieu, A; Bakhouche, BA; Noval, AJ; Mai, A; Guzmán, C; Robert-Masson, L; Iturrioz, X; Hulit, J; Brennan, CH; Hart, IR; Parker, PJ; Ivaska, J; Kermorgant, S
- College Publications