Integrin endosomal signalling suppresses anoikis

Nat Cell Biol. 2015 Nov;17(11):1412-21. doi: 10.1038/ncb3250. Epub 2015 Oct 5.

Abstract

Integrin-containing focal adhesions transmit extracellular signals across the plasma membrane to modulate cell adhesion, signalling and survival. Although integrins are known to undergo continuous endo/exocytic traffic, the potential impact of endocytic traffic on integrin-induced signals is unknown. Here, we demonstrate that integrin signalling is not restricted to cell-ECM adhesions and identify an endosomal signalling platform that supports integrin signalling away from the plasma membrane. We show that active focal adhesion kinase (FAK), an established marker of integrin-ECM downstream signalling, localizes with active integrins on endosomes. Integrin endocytosis positively regulates adhesion-induced FAK activation, which is early endosome antigen-1 and small GTPase Rab21 dependent. FAK binds directly to purified endosomes and becomes activated on them, suggesting a role for endocytosis in enhancing distinct integrin downstream signalling events. Finally, endosomal integrin signalling contributes to cancer-related processes such as anoikis resistance, anchorage independence and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis / genetics
  • Anoikis / physiology*
  • CHO Cells
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Endocytosis / genetics
  • Endocytosis / physiology
  • Endosomes / metabolism*
  • Extracellular Matrix / metabolism
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Focal Adhesions / metabolism
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Mice, Knockout
  • Microscopy, Confocal
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Integrin beta1
  • Focal Adhesion Kinase 1
  • rab GTP-Binding Proteins