GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR INDUCES RET-MEDIATED LAMELLIPODIA FORMATION

Ret is a receptor tyrosine kinase required during embryogenesis for th e survival of enteric and sympathetic neuroblasts. Recently, glial cel l line-derived neurotrophic factor (GDNF) has been identified as a lig and for Ret. We investigated early events in GDNF-induced signal trans duction. 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 stimula tion of an epidermal growth factor receptor-Ret chimeric receptor, res ults in phosphatidylinositol 3-kinase activation and phosphatidylinosi tol 3-kinase-dependent formation of large lamellipodia. Our results in dicate that GDNF can serve as a genuine ligand for Ret. In addition, w e show that GDNF can induce Ret-mediated formation of lamellipodia, ce ll surface protrusions that are implicated in neuritogenesis.