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RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells
SIMPLE SUMMARY: Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression by activating Rac1 in gastric cancer. However, the precise molecular mechanism by which RhoGDI2 activates Rac1 in gastric cancer cells remain...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750349/ https://www.ncbi.nlm.nih.gov/pubmed/35008419 http://dx.doi.org/10.3390/cancers14010255 |
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author | Kim, Hyo-Jin Ryu, Ki-Jun Kim, Minju Kim, Taeyoung Kim, Seon-Hee Han, Hyeontak Kim, Hyemin Hong, Keun-Seok Song, Chae Yeong Choi, Yeonga Hwangbo, Cheol Kim, Kwang Dong Yoo, Jiyun |
author_facet | Kim, Hyo-Jin Ryu, Ki-Jun Kim, Minju Kim, Taeyoung Kim, Seon-Hee Han, Hyeontak Kim, Hyemin Hong, Keun-Seok Song, Chae Yeong Choi, Yeonga Hwangbo, Cheol Kim, Kwang Dong Yoo, Jiyun |
author_sort | Kim, Hyo-Jin |
collection | PubMed |
description | SIMPLE SUMMARY: Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression by activating Rac1 in gastric cancer. However, the precise molecular mechanism by which RhoGDI2 activates Rac1 in gastric cancer cells remains unclear. In this study, we found that interaction between RhoGDI2 and Rac1 is a prerequisite for the recruitment of Rac1 to Filamin A. Moreover, we found that Filamin A acts as a scaffold protein that mediates Rac1 activation. Furthermore, we found that Trio, a Rac1-specific GEF, is critical for Rac1 activation in gastric cancer cells. Conclusively, RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for invasive ability of gastric cancer cells. Our findings suggest that RhoGDI2 might be a potential therapeutic target for reducing gastric cancer cell metastasis. ABSTRACT: Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression in gastric cancer. We previously showed that RhoGDI2 positively regulates Rac1 activity and Rac1 activation is critical for RhoGDI2-induced gastric cancer cell invasion. In this study, to identify the precise molecular mechanism by which RhoGDI2 activates Rac1 activity, we performed two-hybrid screenings using yeast and found that RhoGDI2 plays an important role in the interaction between Rac1, Filamin A and Rac1 activation in gastric cancer cells. Moreover, we found that Filamin A is required for Rac1 activation and the invasive ability of gastric cancer cells. Depletion of Filamin A expression markedly reduced Rac1 activity in RhoGDI2-expressing gastric cancer cells. The migration and invasion ability of RhoGDI2-expressing gastric cancer cells also substantially decreased when Filamin A expression was depleted. Furthermore, we found that Trio, a Rac1-specific guanine nucleotide exchange factor (GEF), is critical for Rac1 activation and the invasive ability of gastric cancer cells. Therefore, we conclude that RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for the invasive ability of gastric cancer cells. |
format | Online Article Text |
id | pubmed-8750349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87503492022-01-12 RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells Kim, Hyo-Jin Ryu, Ki-Jun Kim, Minju Kim, Taeyoung Kim, Seon-Hee Han, Hyeontak Kim, Hyemin Hong, Keun-Seok Song, Chae Yeong Choi, Yeonga Hwangbo, Cheol Kim, Kwang Dong Yoo, Jiyun Cancers (Basel) Article SIMPLE SUMMARY: Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression by activating Rac1 in gastric cancer. However, the precise molecular mechanism by which RhoGDI2 activates Rac1 in gastric cancer cells remains unclear. In this study, we found that interaction between RhoGDI2 and Rac1 is a prerequisite for the recruitment of Rac1 to Filamin A. Moreover, we found that Filamin A acts as a scaffold protein that mediates Rac1 activation. Furthermore, we found that Trio, a Rac1-specific GEF, is critical for Rac1 activation in gastric cancer cells. Conclusively, RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for invasive ability of gastric cancer cells. Our findings suggest that RhoGDI2 might be a potential therapeutic target for reducing gastric cancer cell metastasis. ABSTRACT: Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression in gastric cancer. We previously showed that RhoGDI2 positively regulates Rac1 activity and Rac1 activation is critical for RhoGDI2-induced gastric cancer cell invasion. In this study, to identify the precise molecular mechanism by which RhoGDI2 activates Rac1 activity, we performed two-hybrid screenings using yeast and found that RhoGDI2 plays an important role in the interaction between Rac1, Filamin A and Rac1 activation in gastric cancer cells. Moreover, we found that Filamin A is required for Rac1 activation and the invasive ability of gastric cancer cells. Depletion of Filamin A expression markedly reduced Rac1 activity in RhoGDI2-expressing gastric cancer cells. The migration and invasion ability of RhoGDI2-expressing gastric cancer cells also substantially decreased when Filamin A expression was depleted. Furthermore, we found that Trio, a Rac1-specific guanine nucleotide exchange factor (GEF), is critical for Rac1 activation and the invasive ability of gastric cancer cells. Therefore, we conclude that RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for the invasive ability of gastric cancer cells. MDPI 2022-01-05 /pmc/articles/PMC8750349/ /pubmed/35008419 http://dx.doi.org/10.3390/cancers14010255 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, Hyo-Jin Ryu, Ki-Jun Kim, Minju Kim, Taeyoung Kim, Seon-Hee Han, Hyeontak Kim, Hyemin Hong, Keun-Seok Song, Chae Yeong Choi, Yeonga Hwangbo, Cheol Kim, Kwang Dong Yoo, Jiyun RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title | RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title_full | RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title_fullStr | RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title_full_unstemmed | RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title_short | RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells |
title_sort | rhogdi2-mediated rac1 recruitment to filamin a enhances rac1 activity and promotes invasive abilities of gastric cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750349/ https://www.ncbi.nlm.nih.gov/pubmed/35008419 http://dx.doi.org/10.3390/cancers14010255 |
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