Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes

Dev Cell. 2010 Jul 20;19(1):148-59. doi: 10.1016/j.devcel.2010.06.010.


Cell migration requires endocytosis and recycling of integrins, but it is not known whether degradation of these membrane proteins is involved. Here we demonstrate that in migrating cells, a fraction of the endocytosed fibronectin receptor, alpha 5 beta 1 integrin, is sorted into multivesicular endosomes together with fibronectin and degraded in lysosomes. This sorting requires fibronectin-induced ubiquitination of the alpha 5 subunit, and the activity of the endosomal sorting complex required for transport (ESCRT) machinery, which interacts with alpha 5 beta 1 integrin. Importantly, we demonstrate that both alpha 5 ubiquitination and ESCRT functions are required for proper migration of fibroblasts. We propose that ligand-mediated degradation of alpha 5 beta 1 integrin via the ESCRT pathway is required in order to prevent endosomal accumulation of ligand-bound integrins that might otherwise form nonproductive adhesion sites. Fibronectin and alpha 5 beta 1 integrin therefore are trafficked to lysosomes in a similar way to growth factors and their receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Movement / physiology
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Endosomes / metabolism
  • Endosomes / ultrastructure
  • Fibroblasts / physiology*
  • Fibroblasts / ultrastructure
  • Fibronectins / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Integrin alpha5beta1 / antagonists & inhibitors
  • Integrin alpha5beta1 / chemistry
  • Integrin alpha5beta1 / genetics
  • Integrin alpha5beta1 / metabolism*
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Microscopy, Immunoelectron
  • Protein Binding
  • RNA, Small Interfering / genetics
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Ubiquitination


  • Endosomal Sorting Complexes Required for Transport
  • Fibronectins
  • Integrin alpha5beta1
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins