title: Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression.
abstract: Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Dozynkiewicz
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.forename: Iain
authors.initials: I
authors.lastname: Macpherson
authors.forename: Joan
authors.initials: J
authors.lastname: Grindlay
authors.forename: Peter V E
authors.initials: PV
authors.lastname: van den Berghe
authors.forename: Anne
authors.initials: A
authors.lastname: von Thun
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.forename: Colin J
authors.initials: CJ
authors.lastname: McKay
authors.forename: Ross
authors.initials: R
authors.lastname: Carter
authors.forename: David
authors.initials: D
authors.lastname: Strachan
authors.forename: Kurt
authors.initials: K
authors.lastname: Anderson
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Caswell
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001692:Biological Transport; D015153:Blotting, Western; D002448:Cell Adhesion; D002462:Cell Membrane; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D018450:Disease Progression; D004705:Endocytosis; D011992:Endosomes / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008247:Lysosomes / Q000502:physiology*; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D059027:Recycling; D015398:Signal Transduction; D046888:Tissue Array Analysis; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C117019:CLIC3 protein, human; D018118:Chloride Channels; D039081:Integrin alpha5beta1; D012333:RNA, Messenger; C509763:Rab25 protein, human; D020691:rab GTP-Binding Proteins