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The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer

Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled back to the plasma membrane,...

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Detalles Bibliográficos
Autores principales: Soung, Young Hwa, Ford, Shane, Yan, Cecilia, Chung, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315883/
https://www.ncbi.nlm.nih.gov/pubmed/30545011
http://dx.doi.org/10.3390/cancers10120507
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author Soung, Young Hwa
Ford, Shane
Yan, Cecilia
Chung, Jun
author_facet Soung, Young Hwa
Ford, Shane
Yan, Cecilia
Chung, Jun
author_sort Soung, Young Hwa
collection PubMed
description Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG β4 by inducing NEDD4-dependent ubiquitination of ITG β4 and targeting endosomal ITG β4 into lysosomes. Endocytic recycling of ITG β4 is linked to sorting of ITG β4 into EVs (ITG β4+ EVs). ITG β4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG β4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG β4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG β4 pathway in TNBC.
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spelling pubmed-63158832019-01-09 The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer Soung, Young Hwa Ford, Shane Yan, Cecilia Chung, Jun Cancers (Basel) Article Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG β4 by inducing NEDD4-dependent ubiquitination of ITG β4 and targeting endosomal ITG β4 into lysosomes. Endocytic recycling of ITG β4 is linked to sorting of ITG β4 into EVs (ITG β4+ EVs). ITG β4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG β4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG β4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG β4 pathway in TNBC. MDPI 2018-12-11 /pmc/articles/PMC6315883/ /pubmed/30545011 http://dx.doi.org/10.3390/cancers10120507 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Soung, Young Hwa
Ford, Shane
Yan, Cecilia
Chung, Jun
The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title_full The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title_fullStr The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title_full_unstemmed The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title_short The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer
title_sort role of arrestin domain-containing 3 in regulating endocytic recycling and extracellular vesicle sorting of integrin β4 in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315883/
https://www.ncbi.nlm.nih.gov/pubmed/30545011
http://dx.doi.org/10.3390/cancers10120507
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