Rho guanine nucleotide exchange factor 2

ARHGEF2 (Rho guanine nucleotide exchange factor 2) is a guanine nucleotide exchange factor that activates Rho-GTPases by promoting GDP-to-GTP exchange. Beyond its core catalytic function, it regulates epithelial barrier permeability, cell motility, dendritic spine morphology, and innate immune signaling through interaction with NOD1 and NOD2 receptors during bacterial sensing (UniProt: Q92974).

The protein participates in multiple cellular pathways including NF-κB activation, cytokine secretion in macrophages, and neuronal progenitor cell division and migration. A rare autosomal recessive neurodevelopmental disorder, neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM, MIM 617523), is associated with ARHGEF2 mutations (UniProt: Q92974).

In Alzheimer's disease, ARHGEF2 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2 fold-change −0.565, Chaparral AD proteomics). This finding was replicated across 2 of 4 subcellular fractions in a TMT-labeled differential proteomics experiment, suggesting reduced Rho-GTPase signaling capacity in AD pathology.