Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression

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...

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Published in:Developmental cell Vol. 22; no. 1; p. 131
Main Authors: Dozynkiewicz, Marta A, Jamieson, Nigel B, Macpherson, Iain, Grindlay, Joan, van den Berghe, Peter V E, von Thun, Anne, Morton, Jennifer P, Gourley, Charlie, Timpson, Paul, Nixon, Colin, McKay, Colin J, Carter, Ross, Strachan, David, Anderson, Kurt, Sansom, Owen J, Caswell, Patrick T, Norman, Jim C
Format: Journal Article
Language:English
Published: United States 17.01.2012
Subjects:
Animals
Antibody Formation
Biological Transport
Blotting, Western
Cell Adhesion
Cell Membrane
Cell Movement - physiology
Cells, Cultured
Chloride Channels - genetics
Chloride Channels - immunology
Chloride Channels - metabolism
Dermis - cytology
Dermis - metabolism
Disease Progression
Endocytosis
Endosomes - physiology
Female
Fibroblasts - cytology
Fibroblasts - metabolism
Humans
Immunoenzyme Techniques
Integrin alpha5beta1 - metabolism
Lysosomes - physiology
Neoplasm Metastasis
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Protein Transport
rab GTP-Binding Proteins - genetics
rab GTP-Binding Proteins - immunology
rab GTP-Binding Proteins - metabolism
Rabbits
Real-Time Polymerase Chain Reaction
Recycling
RNA, Messenger - genetics
Signal Transduction
Tissue Array Analysis
ISSN:1878-1551, 1878-1551
Online Access:Get more information
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Summary: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.
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ISSN:1878-1551
1878-1551
DOI:10.1016/j.devcel.2011.11.008