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.