Abstract
Simple SummaryRho 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.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.
Highlights
Gastric cancer is one of the most prevalent malignancies worldwide and the third greatest cause of cancer-related deaths, despite the fact that its incidence and mortality have steadily fallen over the last 10 years [1]
We found that Rho GDP dissociation inhibitor 2 (RhoGDI2) regulates Rac1 activity and that Rac1 activation is required for RhoGDI2-induced gastric cancer cell invasion [18]
To investigate the molecular mechanism by which RhoGDI2 activates Rac1, we searched for novel proteins that interact with RhoGDI2 via yeast two-hybrid screening; we only identified Rac1, which is already known to interact with RhoGDI2 [18]
Summary
Gastric cancer is one of the most prevalent malignancies worldwide and the third greatest cause of cancer-related deaths, despite the fact that its incidence and mortality have steadily fallen over the last 10 years [1]. There are various therapeutic strategies, including surgery, chemotherapy, and radiotherapy, amongst others available for gastric cancer patients. The prognosis remains unsatisfactory, with high mortality [2]. Despite advances in understanding and improved treatments over the last decade, metastasis remains the leading cause of death in cancer patients. Determining the molecular pathways driving gastric cancer metastatic spread could lead to novel treatment targets. Most Rho GTPases work as molecular switches, cycling between a cytosolic inactive
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