Rho guanine nucleotide exchange factor 2 (GEF-H1) (GEF-H1)

Rho guanine nucleotide exchange factor 2 (GEF-H1) is a microtubule-associated protein that acts as a molecular switch, linking the cytoskeleton to intracellular signaling pathways (UniProt Q92974). It is normally sequestered in an inactive form on microtubules, but is released and activated upon microtubule depolymerization (Tonra et al., 2020, BMC Cancer). The small molecule plinabulin exploits this mechanism by binding to tubulin, causing the release of GEF-H1, which subsequently activates the RhoA GTPase (BeyondSpring Pharmaceuticals). This activation leads to the maturation of dendritic cells and the production of pro-inflammatory cytokines, which are essential for mounting an effective anti-tumor immune response and maintaining neutrophil levels during chemotherapy (Blayney et al., 2020, JAMA Oncology). As such, GEF-H1 is a critical mediator of plinabulin's dual-action therapeutic profile as both an immune-oncology agent and a treatment for chemotherapy-induced neutropenia.

Other names

ARHGEF2LFP40Proliferation-associated GEFRho guanine nucleotide exchange factor 2

Plinabulin binds to the colchicine binding site of tubulin, inducing microtubule depolymerization which releases sequestered GEF-H1. The liberated GEF-H1 then activates RhoA, leading to dendritic cell maturation and immune system stimulation (Tonra et al., 2020; BeyondSpring Pharmaceuticals).