ARHGAP18, a member of the RhoGAP gene family, functions as a GTPase-activating protein for RhoA. It cycles RhoA between an active, GTP-bound state and an inactive, GDP-bound state, thereby regulating the actin cytoskeleton. This regulation is crucial for multiple biological processes such as cell shape determination, spreading, motility, angiogenesis, and endothelial cell alignment [3,6,7].

In triple-negative breast cancer (TNBC), ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Higher ARHGAP18 levels in human breast tumors were associated with worse survival outcomes [1]. In hepatocellular carcinoma (HCC), ARHGAP18 overexpression promoted cell proliferation, migration, and invasion [4]. In angiogenesis, loss of ARHGAP18 promoted EC hypersprouting and enhanced tumor vascularization. It acts on RhoC and is important for reaffirming stable EC junctions [2]. In endothelial cells, depletion of ARHGAP18 inhibited alignment in the direction of flow, promoted an inflammatory phenotype, and in double-mutant mice with apolipoprotein E deficiency, led to early-onset atherosclerosis [5]. In thoracic aortic aneurysm (TAA), Arhgap18 global knockout mice exhibited a synthetic, proteolytic, and proinflammatory smooth muscle phenotype and developed TAA more frequently and severely [8].

In conclusion, ARHGAP18 plays essential roles in various biological processes and diseases. Through gene knockout models in mice and other loss-of-function experiments, its roles in cancer metastasis, angiogenesis, endothelial cell function, and aortic aneurysm formation have been revealed. These findings contribute to understanding the mechanisms underlying these disease conditions and may provide potential therapeutic targets.

References:

1. Humphries, Brock, Wang, Zhishan, Li, Yunfei, Jiang, Yiguo, Yang, Chengfeng. 2017. ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA. In Cancer research, 77, 4051-4064. doi:10.1158/0008-5472.CAN-16-3141. https://pubmed.ncbi.nlm.nih.gov/28619708/

2. Chang, Garry H K, Lay, Angelina J, Ting, Ka Ka, Vadas, Mathew A, Gamble, Jennifer R. . ARHGAP18: an endogenous inhibitor of angiogenesis, limiting tip formation and stabilizing junctions. In Small GTPases, 5, 1-15. doi:10.4161/21541248.2014.975002. https://pubmed.ncbi.nlm.nih.gov/25425145/

3. Lombardo, Andrew T, Mitchell, Cameron A R, Zaman, Riasat, McDermitt, David J, Bretscher, Anthony. 2024. ARHGAP18-ezrin functions as an autoregulatory module for RhoA in the assembly of distinct actin-based structures. In eLife, 13, . doi:10.7554/eLife.83526. https://pubmed.ncbi.nlm.nih.gov/38193818/

4. Chen, Ping, Liu, Xiaomeng, Liu, Yayue, Bao, Xu, Wu, Qiang. 2023. ARHGAP18 is Upregulated by Transcription Factor GATA1 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma. In Applied biochemistry and biotechnology, 196, 679-689. doi:10.1007/s12010-023-04459-0. https://pubmed.ncbi.nlm.nih.gov/37171759/

5. Lay, Angelina J, Coleman, Paul R, Formaz-Preston, Ann, Vadas, Mathew A, Gamble, Jennifer R. . ARHGAP18: A Flow-Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis. In Journal of the American Heart Association, 8, e010057. doi:10.1161/JAHA.118.010057. https://pubmed.ncbi.nlm.nih.gov/30630384/

6. Maeda, Masao, Hasegawa, Hitoki, Hyodo, Toshinori, Hamaguchi, Michinari, Senga, Takeshi. 2011. ARHGAP18, a GTPase-activating protein for RhoA, controls cell shape, spreading, and motility. In Molecular biology of the cell, 22, 3840-52. doi:10.1091/mbc.E11-04-0364. https://pubmed.ncbi.nlm.nih.gov/21865595/

7. Coleman, Paul R, Lay, Angelina J, Ting, Ka Ka, Vadas, Mathew A, Gamble, Jennifer R. 2020. YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment. In Cell communication and signaling : CCS, 18, 18. doi:10.1186/s12964-020-0511-7. https://pubmed.ncbi.nlm.nih.gov/32013974/

8. Liu, Renjing, Lo, Lisa, Lay, Angelina J, Vadas, Mathew A, Gamble, Jennifer R. 2017. ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype. In Circulation research, 121, 512-524. doi:10.1161/CIRCRESAHA.117.310692. https://pubmed.ncbi.nlm.nih.gov/28701309/