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Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands

CXCR7 is a receptor for chemokines including CXCL12 (SDF-1), a molecule that promotes tumor growth and metastasis in breast cancer and other malignancies. Building upon the recent observation that CXCR7 sequesters CXCL12, we investigated mechanisms for CXCR7-dependent uptake of chemokines. Breast ca...

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Autores principales: Luker, Kathryn E., Steele, Jessica M., Mihalko, Laura Anne, Ray, Paramita, Luker, Gary D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164491/
https://www.ncbi.nlm.nih.gov/pubmed/20531309
http://dx.doi.org/10.1038/onc.2010.212
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author Luker, Kathryn E.
Steele, Jessica M.
Mihalko, Laura Anne
Ray, Paramita
Luker, Gary D.
author_facet Luker, Kathryn E.
Steele, Jessica M.
Mihalko, Laura Anne
Ray, Paramita
Luker, Gary D.
author_sort Luker, Kathryn E.
collection PubMed
description CXCR7 is a receptor for chemokines including CXCL12 (SDF-1), a molecule that promotes tumor growth and metastasis in breast cancer and other malignancies. Building upon the recent observation that CXCR7 sequesters CXCL12, we investigated mechanisms for CXCR7-dependent uptake of chemokines. Breast cancer cells expressing CXCR7 accumulated chemokines CXCL12 and CXC11 present at concentrations < 1 ng/ml, unlike cells expressing CXCR4. CXCR7-dependent accumulation of chemokines was reduced by inhibitors of clathrin-mediated endocytosis. Following CXCR7-mediated internalization, CXCL12 trafficked to lysosomes and was degraded, although levels of CXCR7 remained stable. CXCR7 reduced CXCL12 in the extracellular space, limiting amounts of chemokine available to acutely stimulate signaling through CXCR4. CXCR7 constitutively internalized and recycled to the cell membrane even in the absence of ligand, and addition of chemokines did not significantly enhance receptor internalization. Chemokines at concentrations less than the Kd for ligand-receptor binding did not alter levels of CXCR7 at the cell surface. Higher concentrations of chemokine ligands reduced total cell surface expression of CXCR7 without affecting receptor internalization, indicating that receptor recycling was inhibited. CXCR7-dependent uptake of chemokines and receptor trafficking were regulated by β-arrestin 2. These studies establish mechanisms through which CXCR7 regulates availability of chemokine ligands in the extracellular space.
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spelling pubmed-31644912011-09-01 Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands Luker, Kathryn E. Steele, Jessica M. Mihalko, Laura Anne Ray, Paramita Luker, Gary D. Oncogene Article CXCR7 is a receptor for chemokines including CXCL12 (SDF-1), a molecule that promotes tumor growth and metastasis in breast cancer and other malignancies. Building upon the recent observation that CXCR7 sequesters CXCL12, we investigated mechanisms for CXCR7-dependent uptake of chemokines. Breast cancer cells expressing CXCR7 accumulated chemokines CXCL12 and CXC11 present at concentrations < 1 ng/ml, unlike cells expressing CXCR4. CXCR7-dependent accumulation of chemokines was reduced by inhibitors of clathrin-mediated endocytosis. Following CXCR7-mediated internalization, CXCL12 trafficked to lysosomes and was degraded, although levels of CXCR7 remained stable. CXCR7 reduced CXCL12 in the extracellular space, limiting amounts of chemokine available to acutely stimulate signaling through CXCR4. CXCR7 constitutively internalized and recycled to the cell membrane even in the absence of ligand, and addition of chemokines did not significantly enhance receptor internalization. Chemokines at concentrations less than the Kd for ligand-receptor binding did not alter levels of CXCR7 at the cell surface. Higher concentrations of chemokine ligands reduced total cell surface expression of CXCR7 without affecting receptor internalization, indicating that receptor recycling was inhibited. CXCR7-dependent uptake of chemokines and receptor trafficking were regulated by β-arrestin 2. These studies establish mechanisms through which CXCR7 regulates availability of chemokine ligands in the extracellular space. 2010-06-07 2010-08-12 /pmc/articles/PMC3164491/ /pubmed/20531309 http://dx.doi.org/10.1038/onc.2010.212 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Luker, Kathryn E.
Steele, Jessica M.
Mihalko, Laura Anne
Ray, Paramita
Luker, Gary D.
Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title_full Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title_fullStr Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title_full_unstemmed Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title_short Constitutive and Chemokine-dependent Internalization and Recycling of CXCR7 in Breast Cancer Cells to Degrade Chemokine Ligands
title_sort constitutive and chemokine-dependent internalization and recycling of cxcr7 in breast cancer cells to degrade chemokine ligands
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164491/
https://www.ncbi.nlm.nih.gov/pubmed/20531309
http://dx.doi.org/10.1038/onc.2010.212
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