title: Regulation of Cell Migration and β1 Integrin Trafficking by the Endosomal Adaptor GGA3.
abstract: The integrin family of cell adhesion receptors link extracellular matrices to intracellular signaling pathways and the actin cytoskeleton; and regulate cell migration, proliferation and survival in normal and diseased tissues. The subcellular location of integrin receptors is critical for their function and deregulated trafficking is implicated in various human diseases. Here we identify a role for Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), in regulating trafficking of β1 integrin. GGA3 knockdown reduces cell surface and total levels of α2, α5 and β1 integrin subunits, inhibits cell spreading, reduces focal adhesion number, as well as cell migration. In the absence of GGA3, integrins are increasingly retained inside the cell, traffic toward the perinuclear lysosomal compartment and their degradation is enhanced. Integrin traffic and maintenance of integrin levels are dependent on the integrity of the Arf binding site of GGA3. Furthermore, sorting nexin 17 (SNX17), a critical regulator of integrin recycling, becomes mislocalized to enlarged late endosomes upon GGA3 depletion. These data support a model whereby GGA3, through its ability to regulate SNX17 endosomal localization and through interaction with Arf6 diverts integrins from the degradative pathway supporting cell migration.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.
authors.forename: Colin D H
authors.initials: CD
authors.lastname: Ratcliffe
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland.
authors.forename: Pranshu
authors.initials: P
authors.lastname: Sahgal
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parachoniak
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, 20520, Finland.|Department of Biochemistry and Food Chemistry, University of Turku, Turku, 20500, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Medicine, McGill University, Montreal, Quebec, H3G 1Y6, Canada.|Department of Oncology, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D058305:Sorting Nexins / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C407306:GGA adaptor proteins; D019012:Integrin beta1; C487895:SNX17 protein, human; D058305:Sorting Nexins; D020727:ADP-Ribosylation Factors
keywords: GGA3; cell migration; endosome; integrin; recycling