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The Journal of Neuroscience, March 1, 2001, 21(5):1464-1472
c-Src Is Required for Glial Cell Line-Derived Neurotrophic Factor
(GDNF) Family Ligand-Mediated Neuronal Survival via a
Phosphatidylinositol-3 Kinase (PI-3K)-Dependent Pathway
Mario
Encinas1, 2,
Malú G.
Tansey2,
Brian A.
Tsui-Pierchala2,
Joan X.
Comella1,
Jeffrey
Milbrandt3, and
Eugene M.
Johnson Jr2
1 Grup de Neurobiologia Molecular, Departament de
Ciències Mèdiques Basiques, Facultat de Medicina,
Universitat de Lleida, 25198 Lleida, Spain, and
2 Departments of Neurology and Molecular Biology and
Pharmacology, and 3 Department of Pathology and Internal
Medicine, Washington University School of Medicine, St. Louis, Missouri
63110
The glial cell line-derived neurotrophic factor (GDNF) family
ligands (GFLs), consisting of GDNF, neurturin, persephin, and artemin,
signal via a multicomponent complex composed of Ret tyrosine kinase and
the glycosyl-phosphatidylinositol (GPI)-anchored coreceptors GFR 1-4. In previous work we have demonstrated that the
localization of Ret to membrane microdomains known as lipid rafts is
essential for GDNF-induced downstream signaling, differentiation, and
neuronal survival. Moreover, we have found that Ret interacts with
members of the Src family kinases (SFK) only when it is localized to
these microdomains. In the present work we show by pharmacological and genetic approaches that Src activity was necessary to elicit optimal GDNF-mediated signaling, neurite outgrowth, and survival. In
particular, p60Src, but not the other ubiquitous SFKs, Fyn and Yes, was
responsible for the observed effects. Moreover, Src appeared to promote
neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway because the PI-3K inhibitor LY294002 prevented GFL-mediated neuronal survival and prevented activated Src-mediated neuronal survival. In contrast, the inhibition of Src activity had no effects on
NGF-mediated survival, indicating that the requirement for Src was
selective for GFL-mediated neuronal survival. These data confirm the
importance of protein-protein interactions between Ret and
raft-associated proteins in the signaling pathways elicited by GDNF,
and the data implicate Src as one of the major signaling molecules
involved in GDNF-mediated bioactivity.
Key words:
Ret; GDNF family ligands (GFLs); Src family kinases
(SFKs); lipid rafts; phosphatidylinositol-3 kinase (PI-3K); cerebellar
granule neurons
Copyright © 2001 Society for Neuroscience 0270-6474/01/2151464-09$05.00/0
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