ARHGEF2 (Rho Guanine Nucleotide Exchange Factor 2), also known as LARG (Leukemia-associated RhoGEF), is a Rho GTPase guanine nucleotide exchange factor that regulates cytoskeletal dynamics, cell migration, and synaptic plasticity. It is involved in neuronal development, dendritic spine formation, and has been implicated in neurodegenerative diseases including Alzheimer's Disease, Parkinson's Disease, and ALS[1].
| Gene Symbol | ARHGEF2 |
| Gene Name | Rho Guanine Nucleotide Exchange Factor 2 (LARG) |
| Chromosome | 1q22 |
| NCBI Gene ID | 9199 |
| OMIM | 607560 |
| Ensembl ID | ENSG00000116584 |
| UniProt | Q9Y5S5 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Miller-Dieker Syndrome |
ARHGEF2 encodes a Rho GEF that activates Rho GTPases, primarily RhoA, but also Rac1 and Cdc42. It links extracellular signals to cytoskeletal reorganization through the RhoA-ROCK pathway.
The RhoA-ROCK pathway is a major regulator of actin-myosin contractility:
Growth factors → GPCRs → ARHGEF2 (LARG) → RhoA → ROCK → MLC phosphorylation
↓
Actin-myosin contraction
Stress fiber formation
Dendritic spine retraction
In neurons, ARHGEF2/ROCK signaling regulates[2]:
ARHGEF2 contributes to synaptic dysfunction in AD through multiple mechanisms[2:1][4]:
RhoA-ROCK pathway is involved in PD pathogenesis[5][6]:
Rho signaling contributes to ALS pathogenesis[8]:
ARHGEF2 is located in the Miller-Dieker syndrome region (1p36). While the primary lissencephaly gene is PAFAH1B1 (LIS1), ARHGEF2 haploinsufficiency may contribute to the phenotype.
ARHGEF2 is expressed throughout the brain:
The ARHGEF2-ROCK pathway is a promising therapeutic target[9]:
Bishop JA, et al. RhoGEFs in neuronal development and disease (2022). 2022. ↩︎
Henderson NT, et al. ARHGEF2 contributes to synaptic dysfunction in Alzheimer's disease (2021). 2021. ↩︎ ↩︎
Momoi T, et al. LARG and microtubule dynamics in neurons (2019). 2019. ↩︎
Yuan J, et al. LARG regulates tau phosphorylation and amyloid-beta toxicity (2022). 2022. ↩︎
Liu W, et al. RhoA activation in dopaminergic neuron degeneration (2022). 2022. ↩︎
Hatase S, et al. Inhibition of RhoA-ROCK pathway protects against alpha-synuclein toxicity (2022). 2022. ↩︎
Cheng H, et al. ARHGEF2 variants in Parkinson's disease genetic risk (2023). 2023. ↩︎
Zhang Y, et al. Rho signaling in amyotrophic lateral sclerosis pathogenesis (2023). 2023. ↩︎
Shimokawa M, et al. ROCK inhibitors in neurological disease (2022). 2022. ↩︎