Glial cell line-derived neurotrophic factor induces Ret-mediated lamellipodia formation.

Ret is a receptor tyrosine kinase required during embryogenesis for the survival of enteric and sympathetic neuroblasts. Recently, glial cell line-derived neurotrophic factor (GDNF) has been identified as a ligand for Ret. We investigated early events in GDNF-induced signal transduction. We show that GDNF activates the Ras-ERK2 signaling pathway in SK-N-MC cells stably transfected with a full-length Ret construct. In addition, activation of Ret tyrosine kinase activity, either via GDNF stimulation of full-length Ret or via epidermal growth factor stimulation of an epidermal growth factor receptor-Ret chimeric receptor, results in phosphatidylinositol 3-kinase activation and phosphatidylinositol 3-kinase-dependent formation of large lamellipodia. Our results indicate that GDNF can serve as a genuine ligand for Ret. In addition, we show that GDNF can induce Ret-mediated formation of lamellipodia, cell surface protrusions that are implicated in neuritogenesis.