Arhgef25, also known as p63RhoGEF and GEFT, encodes Rho guanine nucleotide exchange factors (GEFs) that govern the activation of Rho GTPases, master regulators of the eukaryotic cytoskeleton. It is involved in pathways related to G protein-coupled receptor (GPCR) signaling, especially those mediated by Gαq [1,2,4,6,8]. The gene is of biological importance as it influences processes like cytoskeleton rearrangement, which is crucial for cell motility, division, and tissue development.

Three RhoGEF isoforms are produced by Arhgef25: p63RhoGEF580, GEFT, and p63RhoGEF619. In unstimulated cells, p63RhoGEF580 localizes at the plasma membrane, while p63RhoGEF619 is in the cytoplasm. However, upon activation of Gαq-coupled GPCRs, p63RhoGEF619 relocates to the plasma membrane, and both p63RhoGEF580 and p63RhoGEF619 activate RhoGTPases to a similar extent. Gαq has a dual role in RhoGEF activation, recruiting and allosterically activating cytosolic ARHGEF25 isoforms [1]. Also, miR-190a-3p may be involved in postoperative cognitive dysfunction (POCD) and potentially regulates Arhgef25, among other genes [3]. In glioblastoma, miR-3189-3p can inhibit cell proliferation and migration by directly targeting p63RhoGEF (Arhgef25) [5]. In addition, Arhgef25 was included in a risk score construction for predicting glioblastoma patient prognosis, with the low-risk group having a better prognosis [7].

In conclusion, Arhgef25 is vital for GPCR-mediated Rho GTPase activation and cytoskeleton regulation. Studies related to its isoforms and associated microRNAs in diseases like POCD and glioblastoma enhance our understanding of the gene's role in these disease conditions. These insights from functional studies using genetic models may potentially lead to new therapeutic strategies for such diseases.

References:

1. van Unen, Jakobus, Yin, Taofei, Wu, Yi I, Gadella, Theodorus W J, Goedhart, Joachim. 2016. Kinetics of recruitment and allosteric activation of ARHGEF25 isoforms by the heterotrimeric G-protein Gαq. In Scientific reports, 6, 36825. doi:10.1038/srep36825. https://pubmed.ncbi.nlm.nih.gov/27833100/

2. Lyon, Angeline M, Taylor, Veronica G, Tesmer, John J G. 2013. Strike a pose: Gαq complexes at the membrane. In Trends in pharmacological sciences, 35, 23-30. doi:10.1016/j.tips.2013.10.008. https://pubmed.ncbi.nlm.nih.gov/24287282/

3. Liu, Qiang, Hou, Aisheng, Zhang, Yongyi, Ma, Yunlong, Cao, Jiangbei. 2019. MiR-190a potentially ameliorates postoperative cognitive dysfunction by regulating Tiam1. In BMC genomics, 20, 670. doi:10.1186/s12864-019-6035-0. https://pubmed.ncbi.nlm.nih.gov/31438846/

4. Momotani, Ko, Somlyo, Avril V. 2012. p63RhoGEF: a new switch for G(q)-mediated activation of smooth muscle. In Trends in cardiovascular medicine, 22, 122-7. doi:10.1016/j.tcm.2012.07.007. https://pubmed.ncbi.nlm.nih.gov/22902181/

5. Jeansonne, Duane, DeLuca, Mariacristina, Marrero, Luis, Reiss, Krzysztof, Peruzzi, Francesca. 2015. Anti-tumoral effects of miR-3189-3p in glioblastoma. In The Journal of biological chemistry, 290, 8067-80. doi:10.1074/jbc.M114.633081. https://pubmed.ncbi.nlm.nih.gov/25645911/

6. Bodmann, Eva-Lisa, Wolters, Valerie, Bünemann, Moritz. 2015. Dynamics of G protein effector interactions and their impact on timing and sensitivity of G protein-mediated signal transduction. In European journal of cell biology, 94, 415-9. doi:10.1016/j.ejcb.2015.06.004. https://pubmed.ncbi.nlm.nih.gov/26074197/

7. Zhang, Ao, Guo, Zhen, Ren, Jia-Xin, Zhang, Zhiyun, Wu, Hui. 2023. Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma. In Frontiers in pharmacology, 14, 1162540. doi:10.3389/fphar.2023.1162540. https://pubmed.ncbi.nlm.nih.gov/37538176/

8. Blankenbach, Kira Vanessa, Claas, Ralf Frederik, Aster, Natalie Judith, Wieland, Thomas, Meyer Zu Heringdorf, Dagmar. 2020. Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1. In Cells, 9, . doi:10.3390/cells9102201. https://pubmed.ncbi.nlm.nih.gov/33003441/