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...
| Main Authors: | , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | https://hdl.handle.net/10356/149077 |
| _version_ | 1826118246832537600 |
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| author | Khong, Nicole Zi Jia Lai, Soak-Kuan Koh, Cheng-Gee Geifman-Shochat, Susana Li, Hoi-Yeung |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Khong, Nicole Zi Jia Lai, Soak-Kuan Koh, Cheng-Gee Geifman-Shochat, Susana Li, Hoi-Yeung |
| author_sort | Khong, Nicole Zi Jia |
| collection | NTU |
| 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. |
| first_indexed | 2024-10-01T04:40:16Z |
| format | Journal Article |
| id | ntu-10356/149077 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:40:16Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1490772023-02-28T16:57:03Z A novel function of AAA-ATPase p97/VCP in the regulation of cell motility Khong, Nicole Zi Jia Lai, Soak-Kuan Koh, Cheng-Gee Geifman-Shochat, Susana Li, Hoi-Yeung School of Biological Sciences Science::Biological sciences p97/VCP AAA-ATPase 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. Ministry of Education (MOE) Published version This project is supported by Academic Research Fund RG44/13 and RG44/16, Ministry of Education, Singapore. 2021-06-03T05:33:32Z 2021-06-03T05:33:32Z 2020 Journal Article Khong, N. Z. J., Lai, S., Koh, C., Geifman-Shochat, S. & Li, H. (2020). A novel function of AAA-ATPase p97/VCP in the regulation of cell motility. Oncotarget, 11(1), 74-85. https://dx.doi.org/10.18632/oncotarget.27419 1949-2553 https://hdl.handle.net/10356/149077 10.18632/oncotarget.27419 32002125 2-s2.0-85078794205 1 11 74 85 en RG44/13 RG44/16 Oncotarget © 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. application/pdf |
| spellingShingle | Science::Biological sciences p97/VCP AAA-ATPase Khong, Nicole 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 | Science::Biological sciences p97/VCP AAA-ATPase |
| url | https://hdl.handle.net/10356/149077 |
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