Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3)

Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3, also known as BIG3) is a non-canonical guanine nucleotide exchange factor of the ADP-ribosylation factor (ARF) family, notable for its atypical SEC7 domain structure. ARFGEF3 negatively regulates insulin and glucagon granule biogenesis in pancreatic islet cells, thereby influencing hormone secretion and glucose homeostasis. In breast cancer cells, ARFGEF3/BIG3 sequesters the tumor suppressor PHB2 in the cytoplasm, preventing its nuclear localization and inhibitory effect on estrogen receptor alpha (ERα) signaling, thus promoting estrogen-driven proliferation and therapy resistance. Additionally, ARFGEF3 plays roles in the nervous system, regulating lysosome function and inhibitory synaptic (GABAergic) transmission, and has been genetically linked to neuropsychiatric traits. Its multifaceted roles in endocrine regulation, cancer biology, and neural function make it a prominent candidate for therapeutic intervention and biomarker development, though direct targeting is mainly in preclinical or experimental stages.

Other names

BIG3C6orf92KIAA1244dJ171N11.1PPP1R33Protein phosphatase 1 regulatory subunit 33

Inhibition of BIG3–PHB2 interaction restores nuclear PHB2 function and represses estrogen receptor alpha activity, decreasing endocrine resistance in breast cancer. Inhibition of BIG3 increases insulin and glucagon secretion by enhancing granule biogenesis.