Abstract
Glial cell line-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) are multifunctional signaling molecules in embryogenesis. HGF binds to and activates Met receptor tyrosine kinase. The signaling receptor complex for GDNF typically includes both GDNF family receptor alpha1 (GFRalpha1) and Ret receptor tyrosine kinase. GDNF can also signal independently of Ret via GFRalpha1, although the mechanism has remained unclear. We now show that GDNF partially restores ureteric branching morphogenesis in ret-deficient mice with severe renal hypodysplasia. The mechanism of Ret-independent effect of GDNF was therefore studied by the MDCK cell model. In MDCK cells expressing GFRalpha1 but no Ret, GDNF stimulates branching but not chemotactic migration, whereas both branching and chemotaxis are promoted by GDNF in the cells coexpressing Ret and GFRalpha1, mimicking HGF/Met responses in wild-type MDCK cells. Indeed, GDNF induces Met phosphorylation in several ret-deficient/GFRalpha1-positive and GFRalpha1/Ret-coexpressing cell lines. However, GDNF does not immunoprecipite Met, making a direct interaction between GDNF and Met highly improbable. Met activation is mediated by Src family kinases. The GDNF-induced branching of MDCK cells requires Src activation, whereas the HGF-induced branching does not. Our data show a mechanism for the GDNF-induced branching morphogenesis in non-Ret signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Body Patterning / drug effects
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Body Patterning / genetics
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Chemotaxis / drug effects
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Chemotaxis / genetics
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Dogs
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Drosophila Proteins*
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Hepatocyte Growth Factor / metabolism
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Humans
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Kidney / abnormalities*
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Kidney / cytology
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Kidney / metabolism
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Nerve Growth Factors / metabolism*
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Phosphorylation / drug effects
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-met / metabolism*
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / deficiency
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transfection
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Tumor Cells, Cultured
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Ureter / abnormalities*
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Ureter / cytology
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Ureter / metabolism
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Urothelium / abnormalities*
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Urothelium / drug effects
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Urothelium / metabolism
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src-Family Kinases / metabolism*
Substances
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Drosophila Proteins
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GDNF protein, human
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GFRA1 protein, human
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Nerve Growth Factors
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Proto-Oncogene Proteins
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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src-Family Kinases