GDNF family receptor alpha 3-Proto-oncogene tyrosine-protein kinase receptor Ret complex (GFRα3-RET)

The GDNF family receptor alpha 3-RET (GFRα3-RET) receptor complex is a specialized signaling unit composed of the ligand Artemin, the glycosylphosphatidylinositol (GPI)-anchored co-receptor GFRα3, and the receptor tyrosine kinase RET [1, 11]. This complex is primarily expressed in the sensory neurons of the dorsal root ganglia and plays a critical role in the development of the sympathetic nervous system and the modulation of pain sensitivity [4, 17]. Upon binding of Artemin, GFRα3 facilitates the dimerization and autophosphorylation of RET, which subsequently activates downstream signaling cascades such as the MAPK/ERK and PI3K/Akt pathways [1, 14]. These pathways are known to sensitize nociceptors by modulating the activity of ion channels like TRPV1 and TRPM8, contributing to various forms of chronic, neuropathic, and inflammatory pain [12, 38]. Consequently, the GFRα3-RET complex has emerged as a significant therapeutic target, with monoclonal antibodies like nadecnemab (REGN5069) being developed to block its activity for pain management [25, 30]. Beyond its role in pain, the complex is also implicated in the progression of several cancers, including pancreatic and breast cancer, where it promotes tumor cell invasion and metastasis [11, 16]. While inhibitors are explored for pain and oncology, small molecule agonists are being investigated for their potential neuroprotective and regenerative effects in neurological disorders [3, 20].

Other names

GFRA3-RET complexArtemin receptor complexARTN-GFRα3-RET complexGDNF family receptor alpha 3-RET receptor complexGFR alpha-3-RET complex

Antagonism of the complex (e.g., by nadecnemab) prevents Artemin-induced RET activation and nociceptor sensitization, thereby reducing pain signaling [1, 25]. Agonism (e.g., by BT44 or Artefin) mimics the ligand Artemin to induce RET dimerization and autophosphorylation, promoting survival and regenerative signaling in neurons [3, 14].