Arhgef2, also known as Rho/Rac guanine nucleotide exchange factor 2, is crucial for controlling the spatiotemporal activation of Rho GTPase. It modulates cytoskeleton dynamics, cell division, and cell migration, participating in pathways like RhoA signaling. It is of great biological importance in processes such as hematopoiesis, neural differentiation, and tumor-related developments [1,4,5,6]. Genetic models, especially knockout (KO) mouse models, are valuable for studying its functions.

In a mouse model of inflammatory colorectal cancer, Ythdf1 knockout dampened tumor growth, and YTHDF1 was found to promote ARHGEF2 translation, with ARHGEF2 being a key downstream target regulating RhoA signaling, cell growth, and metastasis [1]. In hepatocellular carcinoma, ER stress up-regulated ARHGEF2 through ZNF263, and ARHGEF2 promoted angiogenesis and treatment resistance via the EDN1 pathway [2]. In prostate cancer, androgen deprivation restored ARHGEF2, promoting neuroendocrine differentiation and treatment resistance [3]. In the cerebral cortex, Arhgef2 knockout decreased Mettl14 expression and total m6A level, reducing m6A methylation of Npdc1 and Cend1, thus impairing neural differentiation [4]. In hematopoietic stem cells, Arhgef2-/-cells showed impaired hematopoietic recovery and increased misoriented divisions, and knockdown in human HSCs also impaired hematopoiesis [5]. In a consanguineous pedigree, a homozygous frameshift mutation in ARHGEF2 caused intellectual disability, midbrain-hindbrain malformation, and mild microcephaly, and Arhgef2 mutant mice recapitulated the human brain malformation [6].

In conclusion, Arhgef2 is essential for multiple biological processes. Its role in diseases such as colorectal cancer, hepatocellular carcinoma, prostate cancer, and neurodevelopmental disorders has been revealed through KO mouse models and other functional studies. Understanding Arhgef2's functions provides insights into disease mechanisms and potential therapeutic targets.