The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers

Abstract

Glial cell line-derived neurotrophic factor family receptor alpha (GFRα) members have been widely connected to the mechanisms contributing to cell growth, differentiation, cell migration and tissue maturation. Here we review GFRα biological functions and discussed the evidence indicating whether GFRα signaling complex present novel opportunities for oncogenic intervention and treatment resistance. Thus, our work systematically reviewed the emerging role of GFRα family members in cancers, and provided novel insights for further researches.

Keywords: GDNF; GFRα1; cancer; neural invasion; treatment resistance.

Figure 1

The GFRα and GFRα-mediated signaling pathways. a The GFRα family consists of four members, GFRα1, GFRα2, GFRα3 and GFRα4, which are tethered to the plasma membrane through GPI anchors containing CRDs. They have four characteristic ligands, namely, GDNF, NRTN, ARTN and PSPN. Two GFL monomers form an entangled homodimer to corresponding GFRα coreceptors. After GFLs and GFRα bind, the complexes associate with RET, a transmembrane tyrosine kinase coreceptor, forming a GFL-GFRα-RET ternary complex. b RET-dependent GFRα signaling is activated via phosphorylation of GFRα on multiple intracellular tyrosines. Two signal transduction pathways contribute to GFL-induced RET activation: via membrane-bound GFRα (cis-signaling) and soluble GFRα (trans-signaling) molecules released from nearby cells. Only the Ras/MAPK and PI3K/Akt signaling pathways are represented in the figure. c The presence of GDNF promotes the association of CFRα with NCAM, resulting in activation of the NCAM-mediated Fyn-FAK-MAPK signaling pathway. Other non-RET receptors of GFRα need further study. LICAM, ligand-induced cell adhesion molecules; NCAM, Neural cell adhesion molecule.

Figure 2

GFRα and treatment resistance. Chemoresistance: Cisplatin stimulates overexpression of GFRα1 via NFκB phosphorylation and decreases cisplatin-induced apoptosis, accompanied by increased autophagy, and significantly promotes cell proliferation through the SRC-AMPK signaling axis. Endocrine resistance: GFLs/GFRα/RET and ER signaling participate in intricate crosstalk via the PI3K/mTOR and RAS/MEK/ERK pathways in breast cancer. Endocrine therapy promotes the expression of GFLs, resulting in a vicious loop of RET signaling. Hypoxia resistance: Hypoxia directly activates ARTN transcription via HIF-1α, and the ARTN-dependent AKT pathway is then activated to trigger expansion of the CSC population. The solid arrows indicate the known and direct interactions between signaling molecules; the broken arrows indicate interactions requiring further investigation. The red arrows indicate the main GFRα signaling pathway.