protein
Rho guanine nucleotide exchange factor 2
Gene
ARHGEF2
Organism
Homo sapiens(9606)
Length
986 aa
Mass
111,543 Da
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.
Generated from the curated entity record below. May contain errors — verify against source links.
Proteomics Evidence · AD
↓ Down in ADP3
-0.690
P2
not detected
S2
not detected
S3
-0.440
Mean log₂FC across detected fractions: -0.565 (2 of 4 fractions detected)
Human post-mortem AD brain vs age-matched controls, TMT-labeled, 4 subcellular fractions (P2, P3, S2, S3), DDA proteomics.
Related Publications
Browse all →Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.
Dujardin Simon et al.Nature medicine2020PMID 32572268Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression.
Bai Bing et al.Neuron2020PMID 31926610A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
Seyfried Nicholas T et al.Cell systems2017PMID 27989508Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Johnson Erik C B et al.Nature neuroscience2022PMID 35115731Organization and regulation of gene transcription.
Cramer PatrickNature2019PMID 31462772
Function
Activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases, which was uniquely reported in PubMed:9857026. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Forms an intracellular sensing system along with NOD1 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIP2 dependent NF-kappaB signaling pathways activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides through NOD1 that is independent of its GEF activity, but also in the activation of NF-kappaB by Shigella effector proteins (IpgB2 and OspB) which requires its GEF activity and the activation of RhoA. Involved in innate immune signaling transduction pathway promoting cytokine IL6/interleukin-6 and TNF secretion in macrophage upon stimulation by bacterial peptidoglycans; acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability (By similarity). Involved in neuronal progenitor cell division and differentiation (PubMed:28453519). Involved in the migration of precerebellar neurons (By similarity)
Disease associations
Neurodevelopmental disorder with midbrain and hindbrain malformationsNEDMHM
An autosomal recessive neurodevelopmental disorder characterized by intellectual disability, speech delay, mild microcephaly, midbrain-hindbrain malformations, and variable dysmorphic features.
Sources
Last updated 5/8/2026, 6:30:10 AM
