Arhgef25, also known as p63RhoGEF and GEFT, is a gene encoding Rho guanine nucleotide exchange factors (GEFs) that play a crucial role in regulating Rho GTPases, master regulators of the eukaryotic cytoskeleton [1,4]. Arhgef25 is involved in Gαq-mediated signaling pathways, which are central to signal transduction from G-protein-coupled receptors (GPCRs) to effectors, influencing intracellular Ca(2+), the actin cytoskeleton, and gene transcription [1,2].

The gene produces three RhoGEF isoforms: p63RhoGEF580, GEFT, and p63RhoGEF619. p63RhoGEF580 is located at the plasma membrane and p63RhoGEF619 is in the cytoplasm in unstimulated cells. However, upon activation of Gαq-coupled GPCRs, p63RhoGEF619 relocates to the plasma membrane. Gαq has a dual role in RhoGEF activation, recruiting and allosterically activating cytosolic ARHGEF25 isoforms [1]. In smooth muscle, p63RhoGEF may act as a new switch for G(q)-mediated activation, playing a role in regulating basal tone and peripheral resistance [4]. In glioblastoma, miR-3189-3p can inhibit cell proliferation and migration by directly targeting p63RhoGEF [5]. In lung mesenchymal stromal cells (LMSCs), the expression of Arhgef25 mRNA was up-regulated, but LMSCs from older mice showed reduced mRNA expression of multiple genes including Arhgef25, along with a decline in proliferative potential and regenerative functions [3].

In conclusion, Arhgef25 is essential for regulating Rho GTPases and is involved in Gαq-mediated signaling, which impacts cytoskeleton regulation, smooth muscle function, and cell processes in glioblastoma and LMSCs. The study of Arhgef25 through in-vivo models helps to understand its role in these biological processes and disease conditions, potentially providing insights for therapeutic strategies.