Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer

Abstract Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 p...

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Autores principales:	Urna Kansakar, Wei Wang, Vesna Markovic, Khalid Sossey-Alaoui
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5b4649c0c4d4b358bb58b34cc1b4a06
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spelling	oai:doaj.org-article:e5b4649c0c4d4b358bb58b34cc1b4a062021-12-02T10:54:06ZPhosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer10.1038/s41598-021-83479-42045-2322https://doaj.org/article/e5b4649c0c4d4b358bb58b34cc1b4a062021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83479-4https://doaj.org/toc/2045-2322Abstract Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 plays a vital role in the progression and metastasis of triple negative breast cancer (TNBC), in part through the regulation of cancer stem cells (CSCs). Several studies have shown that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Moreover, our recent study showed that the proline rich domain (PRD) of WAVE3 is required for maintenance of the CSC niche in breast cancer by regulating the nuclear translocation of the CSC-specific nuclear transcription factor YB1. Here, we show that the PRD domain of WAVE3 and its phosphorylation are essential for driving the oncogenic activity of WAVE3. We show that phosphorylation of WAVE3 PRD is essential for migration and invasion of breast cancer cells in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we show that phosphorylation of the WAVE3 PRD is essential for interaction between WAVE3 and YB1. Loss of PRD phosphorylation inhibits such interaction and the YB1-mediated activation of expression of CSC markers, as well as the WAVE3 mediated activation of EMT. Together, our study identifies a novel role of WAVE3 and its PRD domain in the regulation of the invasion metastasis cascade in BC that is independent of the known function of WAVE3 as an actin cytoskeleton remodeling protein through the WAVE regulatory complex (WRC).Urna KansakarWei WangVesna MarkovicKhalid Sossey-AlaouiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Urna Kansakar Wei Wang Vesna Markovic Khalid Sossey-Alaoui Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
description	Abstract Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 plays a vital role in the progression and metastasis of triple negative breast cancer (TNBC), in part through the regulation of cancer stem cells (CSCs). Several studies have shown that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Moreover, our recent study showed that the proline rich domain (PRD) of WAVE3 is required for maintenance of the CSC niche in breast cancer by regulating the nuclear translocation of the CSC-specific nuclear transcription factor YB1. Here, we show that the PRD domain of WAVE3 and its phosphorylation are essential for driving the oncogenic activity of WAVE3. We show that phosphorylation of WAVE3 PRD is essential for migration and invasion of breast cancer cells in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we show that phosphorylation of the WAVE3 PRD is essential for interaction between WAVE3 and YB1. Loss of PRD phosphorylation inhibits such interaction and the YB1-mediated activation of expression of CSC markers, as well as the WAVE3 mediated activation of EMT. Together, our study identifies a novel role of WAVE3 and its PRD domain in the regulation of the invasion metastasis cascade in BC that is independent of the known function of WAVE3 as an actin cytoskeleton remodeling protein through the WAVE regulatory complex (WRC).
format	article
author	Urna Kansakar Wei Wang Vesna Markovic Khalid Sossey-Alaoui
author_facet	Urna Kansakar Wei Wang Vesna Markovic Khalid Sossey-Alaoui
author_sort	Urna Kansakar
title	Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
title_short	Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
title_full	Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
title_fullStr	Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
title_full_unstemmed	Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer
title_sort	phosphorylation of the proline-rich domain of wave3 drives its oncogenic activity in breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e5b4649c0c4d4b358bb58b34cc1b4a06
work_keys_str_mv	AT urnakansakar phosphorylationoftheprolinerichdomainofwave3drivesitsoncogenicactivityinbreastcancer AT weiwang phosphorylationoftheprolinerichdomainofwave3drivesitsoncogenicactivityinbreastcancer AT vesnamarkovic phosphorylationoftheprolinerichdomainofwave3drivesitsoncogenicactivityinbreastcancer AT khalidsosseyalaoui phosphorylationoftheprolinerichdomainofwave3drivesitsoncogenicactivityinbreastcancer
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Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer

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