A tyrosine-based sorting signal in the β2 integrin cytoplasmic domain mediates its recycling to the plasma membrane and is required for ligand-supported migration

M. Fabbri, L. Fumagalli, G. Bossi, E. Bianchi, J. R. Bender, R. Pardi

Research output: Contribution to journalArticle

Abstract

Integrins play pivotal roles in supporting shear- and mechanical-stress-resistant cell adhesion and migration. These functions require the integrity of the short β subunit cytoplasmic domains, which contain multiple, highly conserved tyrosine-based endocytic signals, typically found in receptors undergoing regulated, clathrin-dependent endocytosis. We hypothesized that these sequences may control surface integrin dynamics in statically adherent and/or locomoting cells via regulated internalization and polarized recycling of the receptors. By using site-directed mutagenesis and ectopic expression of the αL/β2 integrin in Chinese hamster ovary cells, we found that Y735 in the membrane-proximal YRRF sequence is selectively required for recycling of spontaneously internalized receptors to the cell surface and to growth factor-induced membrane ruffles. Disruption of this motif by non-conservative substitutions has no effect on the receptor's adhesive function, but diverts internalized integrins from a recycling compartment into a degradative pathway. Conversely, the non-conservative F754A substitution in the membrane-proximal NPLF sequence abrogates ligand-dependent adhesion and spreading without affecting receptor recycling. Both of these mutants display a severe impairment in ligand-supported migration, suggesting the existence in integrin cytoplasmic domains of independent signals regulating apparently unrelated functions that are required to sustain cell migration over specific ligands.

Original languageEnglish
Pages (from-to)4915-4925
Number of pages11
JournalEMBO Journal
Volume18
Issue number18
DOIs
Publication statusPublished - Sep 15 1999

Keywords

  • Adhesion receptors
  • Cell migration
  • Endocytosis
  • Integrins
  • Protein sorting

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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