Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression

• Published in: Developmental cell Vol. 22; no. 1; pp. 131 - 145
• 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: Cambridge, MA Elsevier Inc 17-01-2012; Cell Press
• Subjects: Animals; Antibody Formation; Biological and medical sciences; Biological Transport; Blotting, Western; Cell Adhesion; Cell differentiation, maturation, development, hematopoiesis; Cell Membrane; Cell Movement - physiology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; 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; Fundamental and applied biological sciences. Psychology; Humans; Immunoenzyme Techniques; Integrin alpha5beta1 - metabolism; Lysosomes - physiology; Molecular and cellular biology; 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; Development; Late; Integrin; Endosome; Lysosome; Tumor progression
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.11.008

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.
► Activated integrins move from late endosomes/lysosomes to the plasma membrane ► Spatial segregation of pathways recycling active and inactive integrins ► CLIC3 regulates cell migration and invasion ► CLIC3 dictates whether Rab25 functions as cancer progression suppressor or promoter