title: Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration.
abstract: Annexins are a family of proteins that bind to phospholipids in a calcium-dependent manner. Earlier studies implicated annexin A6 (AnxA6) to inhibit secretion and participate in the organization of the extracellular matrix. We recently showed that elevated AnxA6 levels significantly reduced secretion of the extracellular matrix protein fibronectin (FN). Because FN is directly linked to the ability of cells to migrate, this prompted us to investigate the role of AnxA6 in cell migration. Up-regulation of AnxA6 in several cell models was associated with reduced cell migration in wound healing, individual cell tracking and three-dimensional migration/invasion assays. The reduced ability of AnxA6-expressing cells to migrate was associated with decreased cell surface expression of αVβ3 and α5β1 integrins, both FN receptors. Mechanistically, we found that elevated AnxA6 levels interfered with syntaxin-6 (Stx6)-dependent recycling of integrins to the cell surface. AnxA6 overexpression caused mislocalization and accumulation of Stx6 and integrins in recycling endosomes, whereas siRNA-mediated AnxA6 knockdown did not modify the trafficking of integrins. Given our recent findings that inhibition of cholesterol export from late endosomes (LEs) inhibits Stx6-dependent integrin recycling and that elevated AnxA6 levels cause LE cholesterol accumulation, we propose that AnxA6 and blockage of LE cholesterol transport are critical for endosomal function required for Stx6-mediated recycling of integrins in cell migration.
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Melero
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Reverter
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Monira
authors.initials: M
authors.lastname: Hoque
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Meneses-Salas
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Meryem
authors.initials: M
authors.lastname: Koese
authors.affiliation: Garvan Institute of Medical Research and Kinghorn Cancer Centre, Cancer Research Program, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: James R W
authors.initials: JR
authors.lastname: Conway
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Johnsen
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Alvarez-Guaita
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Frederic
authors.initials: F
authors.lastname: Morales-Paytuvi
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Yasmin A
authors.initials: YA
authors.lastname: Elmaghrabi
authors.affiliation: Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain, Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain, and.
authors.forename: Albert
authors.initials: A
authors.lastname: Pol
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain, and.
authors.forename: Francesc
authors.initials: F
authors.lastname: Tebar
authors.affiliation: Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4095, Australia.
authors.forename: Rachael Z
authors.initials: RZ
authors.lastname: Murray
authors.affiliation: Garvan Institute of Medical Research and Kinghorn Cancer Centre, Cancer Research Program, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain, and enrich@ub.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia, thomas.grewal@sydney.edu.au.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.affiliation: From the Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain, and carles.rentero@ub.edu.
authors.forename: Carles
authors.initials: C
authors.lastname: Rentero
mesh_terms: D000818:Animals; D017317:Annexin A6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002465:Cell Movement; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003412:Cricetulus; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D050765:Qa-SNARE Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D059008:Time-Lapse Imaging
chemical_list: D017317:Annexin A6; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D050765:Qa-SNARE Proteins; D011994:Recombinant Proteins; D002784:Cholesterol
keywords: SNARE proteins; annexin A6; cell migration; cholesterol; endosome; integrin; integrin recycling; syntaxin 6