GFRα-2 and GFRα-3 Are Two New Receptors for Ligands of the GDNF Family

Abstract

The receptor for glial cell line-derived neurotrophic factor (GDNF) consists of GFR␣-1 and Ret. Neurturin is a GDNF-related neurotrophin whose receptor is presently unknown. Here we report that neurturin can bind to either GFR␣-1 or GFR␣-2, a novel receptor related to GFR␣-1. Both GFR␣-1 and GFR␣-2 mediate neurturininduced Ret phosphorylation. GDNF can also bind to either GFR␣-1 or GFR␣-2, and activate Ret in the presence of either binding receptor. Although both ligands interact with both receptors, cells expressing GFR␣-1 bind GDNF more efficiently than neurturin, while cells expressing GFR␣-2 bind neurturin preferentially. Crosslinking and Ret activation data also suggest that while there is cross-talk, GFR␣-1 is the primary receptor for GDNF and GFR␣-2 exhibits a preference for neurturin. We have also cloned a cDNA that apparently codes for a third member of the GFR␣ receptor family. This putative receptor, designated GFR␣-3, is closely related in amino acid sequence and is nearly identical in the spacing of its cysteine residues to both GFR␣-1 and GFR␣-2. Analysis of the tissue distribution of GFR␣-1, GFR␣-2, GFR␣-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression. Consistent with a role in GDNF function, the GFR␣s and Ret are expressed in many of the same tissues, suggesting that GFR␣s mediate the action of GDNF family ligands in vivo.

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

“…The locus is next to GFRA2 gene. GFRA2 encodes a glycosylphosphatidylinositol (GPI)‐linked cell surface receptor for both glial cell line‐derived neurotrophic factor (GDNF) and neurturin (NTN), but preferentially for NTN (Jing et al., 1997). GDNF and NTN are two structurally related, potent neurotrophic factors that are involved in the control of neuron survival and differentiation (Baudet et al., 2000).…”

Grb2 binding to the different isoforms of Ret tyrosine kinase

“…Ret activation seems to be mediated also by at least two di erent GPI-linked co-receptor proteins, named GDNFR-a1 (Jing et al, 1996;Treanor et al, 1996), -a2 Suvanto et al, 1997) and -a3 (Jing et al, 1997).…”

Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma

“…Recently, another ligand, Enovin (EVN), was described but EVN is identical to ART (Masure et al, 1999). While each ligand preferentially binds to one co-receptor, low a nity interactions with other coreceptors has also been noted for some ligands in vitro Enokido et al, 1998;Jing et al, 1997;Klein et al, 1997;Milbrandt et al, 1998;Sanicola et al, 1997;Trupp et al, 1998). Activation of RET in this manner plays a signi®cant role during human development (Sanchez et al, 1996;Schuchardt et al, 1994) but may also be important during adulthood (Masure et al, 1999).…”

“…Activation of RET in this manner plays a signi®cant role during human development (Sanchez et al, 1996;Schuchardt et al, 1994) but may also be important during adulthood (Masure et al, 1999). There is also growing evidence that RET, each of the ligands and each of the co-receptors are di erentially expressed in a tissuespeci®c and time-speci®c manner (Airaksinen et al, 1999;Baloh et al, 2000;Jing et al, 1997;Masure et al, 1999;Naveilhan et al, 1998;Sanicola et al, 1997).…”

“…One of four related ligands, GDNF, NTN, PSP, and ART, needs to interact with one of four glycosyl-phosphoinositol (GPI)-linked coreceptors, GFRa-1, GFRa-2, GFRa-3 and GFRa-4, before the heterotetrameric complex can bind RET Durbec et al, 1996;Enokido et al, 1998;Jing et al, 1996Jing et al, , 1997Kotzbauer et al, 1996;Milbrandt et al, 1998;Thompson et al, 1998;Trupp et al, 1996). Recently, another ligand, Enovin (EVN), was described but EVN is identical to ART (Masure et al, 1999).…”