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Src in endosomal membranes promotes exosome secretion and tumor progression

c-Src is a membrane-associated tyrosine kinase that has key roles in the signaling transduction that controls cell growth, adhesion, and migration. In the early stage of carcinogenesis, c-Src is activated under the plasma membrane and transduces oncogenic signals. Here we show that c-Src localized t...

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Detalles Bibliográficos
Autores principales: Hikita, Tomoya, Kuwahara, Atsushi, Watanabe, Risayo, Miyata, Mamiko, Oneyama, Chitose
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397170/
https://www.ncbi.nlm.nih.gov/pubmed/30824759
http://dx.doi.org/10.1038/s41598-019-39882-z
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author Hikita, Tomoya
Kuwahara, Atsushi
Watanabe, Risayo
Miyata, Mamiko
Oneyama, Chitose
author_facet Hikita, Tomoya
Kuwahara, Atsushi
Watanabe, Risayo
Miyata, Mamiko
Oneyama, Chitose
author_sort Hikita, Tomoya
collection PubMed
description c-Src is a membrane-associated tyrosine kinase that has key roles in the signaling transduction that controls cell growth, adhesion, and migration. In the early stage of carcinogenesis, c-Src is activated under the plasma membrane and transduces oncogenic signals. Here we show that c-Src localized to the endosomal membrane has unique functions in c-Src–transformed cells. Our results indicate that activated c-Src in the endosomal membrane promoted the secretion of exosomes, in which c-Src was encapsulated. In addition, the ESCRT-interacting molecule, Alix was identified as a c-Src–interacting protein in exosomes. We revealed that the interaction between the SH3 domain of c-Src and the proline-rich region of Alix activates ESCRT–mediated intra-luminal vesicle (ILV) formation, resulting in the upregulation of exosome secretion in c-Src–transformed cells. We observed also a correlation between malignant phenotypes and Alix–dependent aberrant exosome secretion in Src–upregulated cancer cells. Collectively, our findings provide a unique mechanism for the upregulation of exosomes in cancer cells, as well as new insights into the significance of exosome secretion in cancer progression.
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spelling pubmed-63971702019-03-05 Src in endosomal membranes promotes exosome secretion and tumor progression Hikita, Tomoya Kuwahara, Atsushi Watanabe, Risayo Miyata, Mamiko Oneyama, Chitose Sci Rep Article c-Src is a membrane-associated tyrosine kinase that has key roles in the signaling transduction that controls cell growth, adhesion, and migration. In the early stage of carcinogenesis, c-Src is activated under the plasma membrane and transduces oncogenic signals. Here we show that c-Src localized to the endosomal membrane has unique functions in c-Src–transformed cells. Our results indicate that activated c-Src in the endosomal membrane promoted the secretion of exosomes, in which c-Src was encapsulated. In addition, the ESCRT-interacting molecule, Alix was identified as a c-Src–interacting protein in exosomes. We revealed that the interaction between the SH3 domain of c-Src and the proline-rich region of Alix activates ESCRT–mediated intra-luminal vesicle (ILV) formation, resulting in the upregulation of exosome secretion in c-Src–transformed cells. We observed also a correlation between malignant phenotypes and Alix–dependent aberrant exosome secretion in Src–upregulated cancer cells. Collectively, our findings provide a unique mechanism for the upregulation of exosomes in cancer cells, as well as new insights into the significance of exosome secretion in cancer progression. Nature Publishing Group UK 2019-03-01 /pmc/articles/PMC6397170/ /pubmed/30824759 http://dx.doi.org/10.1038/s41598-019-39882-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hikita, Tomoya
Kuwahara, Atsushi
Watanabe, Risayo
Miyata, Mamiko
Oneyama, Chitose
Src in endosomal membranes promotes exosome secretion and tumor progression
title Src in endosomal membranes promotes exosome secretion and tumor progression
title_full Src in endosomal membranes promotes exosome secretion and tumor progression
title_fullStr Src in endosomal membranes promotes exosome secretion and tumor progression
title_full_unstemmed Src in endosomal membranes promotes exosome secretion and tumor progression
title_short Src in endosomal membranes promotes exosome secretion and tumor progression
title_sort src in endosomal membranes promotes exosome secretion and tumor progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397170/
https://www.ncbi.nlm.nih.gov/pubmed/30824759
http://dx.doi.org/10.1038/s41598-019-39882-z
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