title: Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration.
abstract: Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK; Cell Biology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Howe
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK; Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Caswell
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, UK.
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Kurt
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Machesky
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK. Electronic address: j.norman@beatson.gla.ac.uk.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman