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A novel function of AAA-ATPase p97/VCP in the regulation of cell motility

High level of the multifunctional AAA-ATPase p97/VCP is often correlated to the development of cancer; however, the underlying mechanism is not understood completely. Here, we report a novel function of p97/VCP in actin regulation and cell motility. We found that loss of p97/VCP promotes stabilizati...

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Autores principales: Khong, Zi-Jia, Lai, Soak-Kuan, Koh, Cheng-Gee, Geifman-Shochat, Susana, Li, Hoi-Yeung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967774/
https://www.ncbi.nlm.nih.gov/pubmed/32002125
http://dx.doi.org/10.18632/oncotarget.27419
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author Khong, Zi-Jia
Lai, Soak-Kuan
Koh, Cheng-Gee
Geifman-Shochat, Susana
Li, Hoi-Yeung
author_facet Khong, Zi-Jia
Lai, Soak-Kuan
Koh, Cheng-Gee
Geifman-Shochat, Susana
Li, Hoi-Yeung
author_sort Khong, Zi-Jia
collection PubMed
description High level of the multifunctional AAA-ATPase p97/VCP is often correlated to the development of cancer; however, the underlying mechanism is not understood completely. Here, we report a novel function of p97/VCP in actin regulation and cell motility. We found that loss of p97/VCP promotes stabilization of F-actin, which cannot be reversed by actin-destabilizing agent, Cytochalasin D. Live-cell imaging demonstrated reduced actin dynamics in p97/VCP-knockdown cells, leading to compromised cell motility. We further examined the underlying mechanism and found elevated RhoA protein levels along with increased phosphorylation of its downstream effectors, ROCK, LIMK, and MLC upon the knockdown of p97/VCP. Since p97/VCP is indispensable in the ubiquitination-dependent protein degradation pathway, we investigated if the loss of p97/VCP hinders the protein degradation of RhoA. Knockdown of p97/VCP resulted in a higher amount of ubiquitinated RhoA, suggesting p97/VCP involvement in the proteasome-dependent protein degradation pathway. Finally, we found that p97/VCP interacts with FBXL19, a molecular chaperone known to guide ubiquitinated RhoA for proteasomal degradation. Reduction of p97/VCP may result in the accumulation of RhoA which, in turn, enhances cytoplasmic F-actin formation. In summary, our study uncovered a novel function of p97/VCP in actin regulation and cell motility via the Rho-ROCK dependent pathway which provides fundamental insights into how p97/VCP is involved in cancer development.
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spelling pubmed-69677742020-01-30 A novel function of AAA-ATPase p97/VCP in the regulation of cell motility Khong, Zi-Jia Lai, Soak-Kuan Koh, Cheng-Gee Geifman-Shochat, Susana Li, Hoi-Yeung Oncotarget Research Paper High level of the multifunctional AAA-ATPase p97/VCP is often correlated to the development of cancer; however, the underlying mechanism is not understood completely. Here, we report a novel function of p97/VCP in actin regulation and cell motility. We found that loss of p97/VCP promotes stabilization of F-actin, which cannot be reversed by actin-destabilizing agent, Cytochalasin D. Live-cell imaging demonstrated reduced actin dynamics in p97/VCP-knockdown cells, leading to compromised cell motility. We further examined the underlying mechanism and found elevated RhoA protein levels along with increased phosphorylation of its downstream effectors, ROCK, LIMK, and MLC upon the knockdown of p97/VCP. Since p97/VCP is indispensable in the ubiquitination-dependent protein degradation pathway, we investigated if the loss of p97/VCP hinders the protein degradation of RhoA. Knockdown of p97/VCP resulted in a higher amount of ubiquitinated RhoA, suggesting p97/VCP involvement in the proteasome-dependent protein degradation pathway. Finally, we found that p97/VCP interacts with FBXL19, a molecular chaperone known to guide ubiquitinated RhoA for proteasomal degradation. Reduction of p97/VCP may result in the accumulation of RhoA which, in turn, enhances cytoplasmic F-actin formation. In summary, our study uncovered a novel function of p97/VCP in actin regulation and cell motility via the Rho-ROCK dependent pathway which provides fundamental insights into how p97/VCP is involved in cancer development. Impact Journals LLC 2020-01-07 /pmc/articles/PMC6967774/ /pubmed/32002125 http://dx.doi.org/10.18632/oncotarget.27419 Text en http://creativecommons.org/licenses/by/3.0/ Copyright: Khong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Khong, Zi-Jia
Lai, Soak-Kuan
Koh, Cheng-Gee
Geifman-Shochat, Susana
Li, Hoi-Yeung
A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title_full A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title_fullStr A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title_full_unstemmed A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title_short A novel function of AAA-ATPase p97/VCP in the regulation of cell motility
title_sort novel function of aaa-atpase p97/vcp in the regulation of cell motility
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967774/
https://www.ncbi.nlm.nih.gov/pubmed/32002125
http://dx.doi.org/10.18632/oncotarget.27419
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