Arhgef11, also known as Rho guanine nucleotide exchange factor 11, is a key regulator in various biological processes. It is a Rho -specific guanine nucleotide exchange factor that activates Rho GTPases, which are crucial for cytoskeletal dynamics. This activation is involved in multiple pathways such as the β -catenin, Rho -ROCK, and insulin signaling pathways, influencing cell proliferation, migration, and epithelial-mesenchymal transition (EMT), and playing an important role in normal physiological functions and disease development [1,3,5,6,7].

In hepatocellular carcinoma (HCC), knockdown of ARHGEF11 in HCCLM3 and SKHEP1 cell lines inhibited cell proliferation and invasion, and attenuated β -catenin nuclear translocation, EMT, and cell cycle progression, suggesting its promoting role in HCC progression via the β -catenin pathway [1]. In the Dahl salt-sensitive rat (a model for hypertension-related chronic kidney disease), loss of Arhgef11 protected against hypertension-induced renal injury, with reduced proteinuria and fibrosis. Omics data showed early transcriptome/protein changes in the cytoskeleton as early as week 4, impacting cellular functions like actin cytoskeletal regulation [2]. In epithelial cells, ablation of Esrp1/2 led to loss of the epithelial isoform of Arhgef11, impairing epithelial tight junction integrity, and only the epithelial Arhgef11 isoform could rescue myosin light chain phosphorylation in Arhgef11 KO epithelial cells [4].

In summary, Arhgef11 is essential for processes like cell proliferation, migration, and maintaining epithelial tight junction integrity. Studies using gene knockout models in rats and cell lines have revealed its role in diseases such as HCC, hypertension-induced renal injury, and potentially fetal macrosomia and transgenerational obesity. These findings contribute to understanding disease mechanisms and may help identify Arhgef11 as a potential biomarker or therapeutic target for these disease areas [1,2,4-6].

References:

1. Du, Jinpeng, Zhu, Zexin, Xu, Lin, Yuan, Kefei, Zeng, Yong. 2020. ARHGEF11 promotes proliferation and epithelial-mesenchymal transition of hepatocellular carcinoma through activation of β-catenin pathway. In Aging, 12, 20235-20253. doi:10.18632/aging.103772. https://pubmed.ncbi.nlm.nih.gov/33122451/

2. Johnson, Ashley C, Wu, Wenjie, Attipoe, Esinam M, Lindsey, Merry L, Garrett, Michael R. 2020. Loss of Arhgef11 in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury. In Hypertension (Dallas, Tex. : 1979), 75, 1012-1024. doi:10.1161/HYPERTENSIONAHA.119.14338. https://pubmed.ncbi.nlm.nih.gov/32148127/

3. Nanda, Suchet, Calderon, Abram, Sachan, Arya, Nalbant, Perihan, Dehmelt, Leif. 2023. Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles. In Nature communications, 14, 8356. doi:10.1038/s41467-023-43875-y. https://pubmed.ncbi.nlm.nih.gov/38102112/

4. Lee, SungKyoung, Cieply, Benjamin, Yang, Yueqin, Chan, Patricia, Carstens, Russ P. . Esrp1-Regulated Splicing of Arhgef11 Isoforms Is Required for Epithelial Tight Junction Integrity. In Cell reports, 25, 2417-2430.e5. doi:10.1016/j.celrep.2018.10.097. https://pubmed.ncbi.nlm.nih.gov/30485810/

5. Zhang, Wanyi, Su, Rina, Lin, Li, Yang, Huixia. 2017. ARHGEF11 affecting the placental insulin signaling pathway in fetal macrosomia of normal glucose tolerance pregnant women. In Placenta, 63, 7-14. doi:10.1016/j.placenta.2017.12.010. https://pubmed.ncbi.nlm.nih.gov/29486856/

6. Zhang, Wanyi, Su, Rina, Feng, Hui, Wang, Chen, Yang, Huixia. 2019. Transgenerational Obesity and Alteration of ARHGEF11 in the Rat Liver Induced by Intrauterine Hyperglycemia. In Journal of diabetes research, 2019, 6320839. doi:10.1155/2019/6320839. https://pubmed.ncbi.nlm.nih.gov/31612150/

7. Jia, Zhen, Johnson, Ashley C, Wang, Xuexiang, Kyle, Patrick B, Garrett, Michael R. 2015. Allelic Variants in Arhgef11 via the Rho-Rock Pathway Are Linked to Epithelial-Mesenchymal Transition and Contributes to Kidney Injury in the Dahl Salt-Sensitive Rat. In PloS one, 10, e0132553. doi:10.1371/journal.pone.0132553. https://pubmed.ncbi.nlm.nih.gov/26172442/