Cell Reports (Jan 2015)

Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration

  • Elena Rainero,
  • Jonathan D. Howe,
  • Patrick T. Caswell,
  • Nigel B. Jamieson,
  • Kurt Anderson,
  • David R. Critchley,
  • Laura Machesky,
  • Jim C. Norman

DOI
https://doi.org/10.1016/j.celrep.2014.12.037
Journal volume & issue
Vol. 10, no. 3
pp. 398 – 413

Abstract

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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.