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The Mouse Soluble GFRalpha4 Receptor Activates RET Independently of Its Ligand Persephin

The Mouse Soluble GFRalpha4 Receptor Activates RET Independently of Its Ligand Persephin

J Yang, P Runeberg-Roos, V-M Leppänen, M Saarma

Oncogene. 2007 May 31;26(26):3892-8.

PMID: 17213820

Abstract:

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 (GFRalphas) 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 GFRalpha4 receptor may have a potentially modifying role in MEN 2. Several naturally occurring, different splice variants of the mammalian GFRalpha4 have been reported. A 7 bp insertion-mutation in the human GFRalpha4 gene causes a shift of reading frame and thereby changes the balance between the transcripts encoding GPI-anchored and soluble GFRalpha4 receptors. We report here that the mammalian soluble GFRalpha4 can activate RET independently of its preferential ligand, persephin. Our data show that soluble GFRalpha4 can associate with, and induce, phosphorylation of RET. In addition, our data show that this isoform of GFRalpha4 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, GFRalpha4 may be a candidate gene for, or modifier of, the MEN 2 diseases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248823	Persephin human			Price

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