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Published online 7 April 2003. doi:10.1083/jcb.200212174
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© The Rockefeller University Press, 0021-9525/2003/4/119 $5.00
The Journal of Cell Biology, Volume 161, Number 1, 119-129

Article

GDNF promotes tubulogenesis of GFR{alpha}1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase



Anna Popsueva1, Dmitry Poteryaev2, Elena Arighi1, Xiaojuan Meng1, Alexandre Angers-Loustau3, David Kaplan3, Mart Saarma2 and Hannu Sariola1,4

1 Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki
2 Institute of Biotechnology, Program for Molecular Neurobiology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland
3 Brain Tumour Research Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4
4 HUCH Diagnostics, Helsinki University Central Hospital, FIN-00029, Helsinki, Finland

Address correspondence to Hannu Sariola, Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, FIN-00014 Helsinki, Finland. Tel.: 35-89-19125140. Fax: 35-89-19125235. E-mail: Hannu.Sariola{at}helsinki.fi

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 {alpha}1 (GFR{alpha}1) and Ret receptor tyrosine kinase. GDNF can also signal independently of Ret via GFR{alpha}1, 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 GFR{alpha}1 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 GFR{alpha}1, mimicking HGF/Met responses in wild-type MDCK cells. Indeed, GDNF induces Met phosphorylation in several ret-deficient/GFR{alpha}1-positive and GFR{alpha}1/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.

Key Words: GDNF; branching morphogenesis; Met; Src; GFR{alpha}1

* Abbreviations used in this paper: DN, dominant-negative; E, embryonic day; GDNF, glial cell line–derived neurotrophic factor; GFR{alpha}1, GDNF family receptor {alpha}1; GPI, glycosylphosphatidylinositol; HGF, hepatocyte growth factor.


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