GDNF promotes tubulogenesis of GFRα1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase

Autor: Anna E. Popsueva, Mart Saarma, Hannu Sariola, Alexandre Angers-Loustau, David L. Kaplan, Elena Arighi, Xiaojuan Meng, Dmitry Poteryaev
Rok vydání: 2003
Předmět:
Receptor complex
Cell signaling
Glial Cell Line-Derived Neurotrophic Factor Receptors
endocrine system diseases
animal diseases
GDNF
branching morphogenesis
Met
Src
GFRα1
Kidney
Transfection
Article
03 medical and health sciences
Dogs
0302 clinical medicine
Proto-Oncogene Proteins
Tumor Cells
Cultured
Glial cell line-derived neurotrophic factor
medicine
Animals
Drosophila Proteins
Humans
Glial Cell Line-Derived Neurotrophic Factor
Nerve Growth Factors
Phosphorylation
Body Patterning
030304 developmental biology
0303 health sciences
biology
Hepatocyte Growth Factor
urogenital system
Chemotaxis
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
Cell Differentiation
Cell Biology
Proto-Oncogene Proteins c-met
Cell biology
src-Family Kinases
nervous system
biology.protein
Cancer research
Hepatocyte growth factor
Ureter
Urothelium
Signal transduction
GDNF family of ligands
030217 neurology & neurosurgery
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
medicine.drug
Zdroj: The Journal of Cell Biology
ISSN: 1540-8140
0021-9525
Popis: 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.
Databáze: OpenAIRE
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