Oncotarget

Research Papers:

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

Zi-Jia Khong, Soak-Kuan Lai, Cheng-Gee Koh, Susana Geifman-Shochat and Hoi-Yeung Li _

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Abstract

Zi-Jia Khong1, Soak-Kuan Lai1, Cheng-Gee Koh1, Susana Geifman-Shochat1 and Hoi-Yeung Li1

1 School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Singapore

Correspondence to:

Hoi-Yeung Li,email: hyli@ntu.edu.sg

Keywords: p97/VCP; AAA-ATPase; ROCK; RhoA; cell motility

Received: August 19, 2019     Accepted: December 21, 2019     Published: January 07, 2020

ABSTRACT

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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