GFRA3

GFRA3 (GDNF Family Receptor Alpha 3), also known as GFRα3, is a glycosylphosphatidylinositol (GPI)-anchored cell surface receptor that binds to artemin (ARTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family. It forms a signaling complex with the RET proto-oncogene receptor tyrosine kinase, activating downstream pathways such as MAPK/ERK and PI3K/AKT. This receptor-ligand interaction is critical for the development and maintenance of specific neuronal populations, particularly nociceptive sensory neurons and sympathetic neurons. GFRA3-mediated signaling also regulates cell migration, survival, and differentiation, with cross-talk involving NCAM and integrins.
Dysregulation of GFRA3 is implicated in neuropathic pain syndromes, neuroblastoma, and Hirschsprung's disease. Overexpression of GFRA3-RET complexes has been observed in pancreatic and breast cancers, driving tumor progression via sustained oncogenic signaling. Current therapeutic strategies target the ARTN-GFRA3-RET axis using small-molecule RET inhibitors (e.g., selpercatinib) and monoclonal antibodies. Preclinical studies demonstrate that GFRA3 blockade alleviates chemotherapy-induced neuropathy and inhibits metastasis in RET-fusion-positive cancers. A phase II trial (NCT04211372) is evaluating GFRA3-targeted therapy in neuroendocrine tumors.