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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| Vydáno v: | Developmental cell Ročník 22; číslo 1; s. 131 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
17.01.2012
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| ISSN: | 1878-1551, 1878-1551 |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Sansom, Owen J Dozynkiewicz, Marta A Norman, Jim C Strachan, David Carter, Ross Nixon, Colin McKay, Colin J van den Berghe, Peter V E Morton, Jennifer P Jamieson, Nigel B Macpherson, Iain Caswell, Patrick T Anderson, Kurt von Thun, Anne Grindlay, Joan Gourley, Charlie Timpson, Paul |
| Author_xml | – sequence: 1 givenname: Marta A surname: Dozynkiewicz fullname: Dozynkiewicz, Marta A organization: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK – sequence: 2 givenname: Nigel B surname: Jamieson fullname: Jamieson, Nigel B – sequence: 3 givenname: Iain surname: Macpherson fullname: Macpherson, Iain – sequence: 4 givenname: Joan surname: Grindlay fullname: Grindlay, Joan – sequence: 5 givenname: Peter V E surname: van den Berghe fullname: van den Berghe, Peter V E – sequence: 6 givenname: Anne surname: von Thun fullname: von Thun, Anne – sequence: 7 givenname: Jennifer P surname: Morton fullname: Morton, Jennifer P – sequence: 8 givenname: Charlie surname: Gourley fullname: Gourley, Charlie – sequence: 9 givenname: Paul surname: Timpson fullname: Timpson, Paul – sequence: 10 givenname: Colin surname: Nixon fullname: Nixon, Colin – sequence: 11 givenname: Colin J surname: McKay fullname: McKay, Colin J – sequence: 12 givenname: Ross surname: Carter fullname: Carter, Ross – sequence: 13 givenname: David surname: Strachan fullname: Strachan, David – sequence: 14 givenname: Kurt surname: Anderson fullname: Anderson, Kurt – sequence: 15 givenname: Owen J surname: Sansom fullname: Sansom, Owen J – sequence: 16 givenname: Patrick T surname: Caswell fullname: Caswell, Patrick T – sequence: 17 givenname: Jim C surname: Norman fullname: Norman, Jim C |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22197222$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression |
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