The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) all signal through the transmembrane receptor tyrosine kinase RET. The signalling complex consists of GFLs, GPI-anchored ligand binding GDNF family receptor alphas (GFRs) and RET. Signalling via RET is required for the development of the nervous system and the kidney, as well as for spermatogenesis. However, constitutive activation of RET is implicated as a cause in several diseases. Mutations of the RET proto-oncogene cause the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). Recently, it has been suggested that mutations in the persephin binding GFR4 receptor may have a potentially modifying role in MEN 2. Several naturally occurring, different splice variants of the mammalian GFR4 have been reported. A 7 bp insertion–mutation in the human GFR4 gene causes a shift of reading frame and thereby changes the balance between the transcripts encoding GPI-anchored and soluble GFR4 receptors. We report here that the mammalian soluble GFR4 can activate RET independently of its preferential ligand, persephin. Our data show that soluble GFR4 can associate with, and induce, phosphorylation of RET. In addition, our data show that this isoform of GFR4 can induce downstream signalling, as well as neuronal survival and differentiation, in the absence of persephin. These results suggest that, in line with the previous report, GFR4 may be a candidate gene for, or modifier of, the MEN 2 diseases.