The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles

Abstract Metastasis, the hallmark of cancer propagation is attributed by the modification of phenotypic/functional behavior of cells to break attachment and migrate to distant body parts. Cancer cell-secreted microvesicles (MVs) contribute immensely in disease propagation. These nano-vesicles, gener...

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Autores principales:	Kaushik Das, Ramesh Prasad, Sreetama Roy, Ashis Mukherjee, Prosenjit Sen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c36d4520a4049b1bbed04fbec059933
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spelling	oai:doaj.org-article:7c36d4520a4049b1bbed04fbec0599332021-12-02T11:41:13ZThe Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles10.1038/s41598-018-25725-w2045-2322https://doaj.org/article/7c36d4520a4049b1bbed04fbec0599332018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25725-whttps://doaj.org/toc/2045-2322Abstract Metastasis, the hallmark of cancer propagation is attributed by the modification of phenotypic/functional behavior of cells to break attachment and migrate to distant body parts. Cancer cell-secreted microvesicles (MVs) contribute immensely in disease propagation. These nano-vesicles, generated from plasma membrane outward budding are taken up by nearby healthy cells thereby inducing phenotypic alterations in those recipient cells. Protease activated receptor 2 (PAR2), activated by trypsin, also contributes to cancer progression by increasing metastasis, angiogenesis etc. Here, we report that PAR2 activation promotes pro-metastatic MVs generation from human breast cancer cell line, MDA-MB-231. Rab5a, located at the plasma membrane plays vital roles in MVs biogenesis. We show that PAR2 stimulation promotes AKT phosphorylation which activates Rab5a by converting inactive Rab5a-GDP to active Rab5a-GTP. Active Rab5a polymerizes actin which critically regulates MVs shedding. Not only MVs generation, has this Rab5a activation also promoted cell migration and invasion. We reveal that Rab5a is over-expressed in human breast tumor specimen and contributes MVs generation in those patients. The involvement of p38 MAPK in MVs-induced cell metastasis has also been highlighted in the present study. Blockade of Rab5a activation can be a potential therapeutic approach to restrict MVs shedding and associated breast cancer metastasis.Kaushik DasRamesh PrasadSreetama RoyAshis MukherjeeProsenjit SenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kaushik Das Ramesh Prasad Sreetama Roy Ashis Mukherjee Prosenjit Sen The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
description	Abstract Metastasis, the hallmark of cancer propagation is attributed by the modification of phenotypic/functional behavior of cells to break attachment and migrate to distant body parts. Cancer cell-secreted microvesicles (MVs) contribute immensely in disease propagation. These nano-vesicles, generated from plasma membrane outward budding are taken up by nearby healthy cells thereby inducing phenotypic alterations in those recipient cells. Protease activated receptor 2 (PAR2), activated by trypsin, also contributes to cancer progression by increasing metastasis, angiogenesis etc. Here, we report that PAR2 activation promotes pro-metastatic MVs generation from human breast cancer cell line, MDA-MB-231. Rab5a, located at the plasma membrane plays vital roles in MVs biogenesis. We show that PAR2 stimulation promotes AKT phosphorylation which activates Rab5a by converting inactive Rab5a-GDP to active Rab5a-GTP. Active Rab5a polymerizes actin which critically regulates MVs shedding. Not only MVs generation, has this Rab5a activation also promoted cell migration and invasion. We reveal that Rab5a is over-expressed in human breast tumor specimen and contributes MVs generation in those patients. The involvement of p38 MAPK in MVs-induced cell metastasis has also been highlighted in the present study. Blockade of Rab5a activation can be a potential therapeutic approach to restrict MVs shedding and associated breast cancer metastasis.
format	article
author	Kaushik Das Ramesh Prasad Sreetama Roy Ashis Mukherjee Prosenjit Sen
author_facet	Kaushik Das Ramesh Prasad Sreetama Roy Ashis Mukherjee Prosenjit Sen
author_sort	Kaushik Das
title	The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
title_short	The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
title_full	The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
title_fullStr	The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
title_full_unstemmed	The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles
title_sort	protease activated receptor2 promotes rab5a mediated generation of pro-metastatic microvesicles
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/7c36d4520a4049b1bbed04fbec059933
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The Protease Activated Receptor2 Promotes Rab5a Mediated Generation of Pro-metastatic Microvesicles

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