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.
van Weering
D H
DH
Laboratory for Physiological Chemistry, Graduate School for Developmental Biology, Utrecht University, The Netherlands.
Bos
J L
JL
D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000730:Androstadienes / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D029721:Drosophila Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016501:Neurites / Q000648:ultrastructure*; D009474:Neurons / Q000648:ultrastructure*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000077191:Wortmannin