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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.
Highlights
The Valosin Containing Protein (VCP), known as p97, is one of the most extensively studied type II adenosine triphosphatase (ATPase) Associated with a variety of Activities (AAA) [1, 2]
We showed that p97/VCP is implicated in cell migration, through alterations in the Rho-Rho-associated protein kinase (ROCK) pathway
We found that p97/VCP may be implicated in cancer cell migration properties, which are consistent with prominent findings stating that an increase in p97/VCP expression positively correlates with the invasiveness of most tumor cells [4]
Summary
The Valosin Containing Protein (VCP), known as p97, is one of the most extensively studied type II ATPase Associated with a variety of Activities (AAA) [1, 2]. The Rho-ROCK pathway is central to actin cytoskeleton homeostasis through the phosphorylation of the ROCK protein’s downstream targets [18, 19]. ROCK signaling is implicated in the control of cell motility, and it is integral in physiological processes such as wound healing and cell migration [21]. We showed that p97/VCP is implicated in cell migration, through alterations in the Rho-ROCK pathway. Our results revealed a novel functional role of p97/VCP in the regulation of cell migration and its underlying molecular mechanism. We found that p97/VCP may be implicated in cancer cell migration properties, which are consistent with prominent findings stating that an increase in p97/VCP expression positively correlates with the invasiveness of most tumor cells [4]
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