PSPN/GFRα4 has a significantly weaker capacity than GDNF/GFRα1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth

Previously, it was shown that the recruitment of RET into lipid rafts by glial cell line-derived neurotrophic factor (GDNF)/GFRα1 is crucial for efficient signal transduction. Here, we show that the mouse GFRα4 is a functional, N-glycosylated, glycosylphosphatidylinositol (GPI)-anchored protein, which mediates persephin (PSPN)-induced phosphorylation of RET, but has an almost undetectable capacity to recruit RET into the 0.1% Triton X-100 insoluble membrane fraction. In spite of this, PSPN/mGFRα4 promotes neurite outgrowth in PC6-3 cells and survival of cerebellar granule neurons. As we show that also human PSPN/GFRα4 is unable to recruit RET into lipid rafts, we propose that the mammalian GFRα4 in this respect differs from GFRα1.