Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes.
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.
Lobert
Viola Hélène
VH
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
Brech
Andreas
A
Pedersen
Nina Marie
NM
Wesche
Jørgen
J
Oppelt
Angela
A
Malerød
Lene
L
Stenmark
Harald
H
D001483:Base Sequence; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000502:physiology* / Q000648:ultrastructure; D005353:Fibronectins / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D016253:Microscopy, Immunoelectron; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination
D056827:Endosomal Sorting Complexes Required for Transport; D005353:Fibronectins; D039081:Integrin alpha5beta1; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins