 |
 Previous Article | Next Article 
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
This article has been cited by other articles:
|
|
|
|
 
T.-J. Kao, E. Palmesino, and A. Kania
Src Family Kinases Are Required for Limb Trajectory Selection by Spinal Motor Axons
J. Neurosci.,
April 29, 2009;
29(17):
5690 - 5700.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-L. Chen, I-H. Liu, S. J. Fliesler, X. Han, S. S. Huang, and J. S. Huang
Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis
J. Cell Sci.,
October 15, 2007;
120(20):
3509 - 3521.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Oatley, M. R. Avarbock, and R. L. Brinster
Glial Cell Line-derived Neurotrophic Factor Regulation of Genes Essential for Self-renewal of Mouse Spermatogonial Stem Cells Is Dependent on Src Family Kinase Signaling
J. Biol. Chem.,
August 31, 2007;
282(35):
25842 - 25851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Paveliev, M. Lume, A. Velthut, M. Phillips, U. Arumae, and M. Saarma
Neurotrophic factors switch between two signaling pathways that trigger axonal growth
J. Cell Sci.,
August 1, 2007;
120(15):
2507 - 2516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Asai, T. Fukuda, Z. Wu, A. Enomoto, V. Pachnis, M. Takahashi, and F. Costantini
Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells
Development,
November 15, 2006;
133(22):
4507 - 4516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Elitt, S. L. McIlwrath, J. J. Lawson, S. A. Malin, D. C. Molliver, P. K. Cornuet, H. R. Koerber, B. M. Davis, and K. M. Albers
Artemin Overexpression in Skin Enhances Expression of TRPV1 and TRPA1 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Heat and Cold.
J. Neurosci.,
August 15, 2006;
26(33):
8578 - 8587.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Malin, D. C. Molliver, H. R. Koerber, P. Cornuet, R. Frye, K. M. Albers, and B. M. Davis
Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize Nociceptors In Vitro and Produce Thermal Hyperalgesia In Vivo.
J. Neurosci.,
August 15, 2006;
26(33):
8588 - 8599.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra
RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors
Endocr. Rev.,
August 1, 2006;
27(5):
535 - 560.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Hauck, N. Kinkl, C. A. Deeg, M. Swiatek-de Lange, S. Schoffmann, and M. Ueffing
GDNF Family Ligands Trigger Indirect Neuroprotective Signaling in Retinal Glial Cells.
Mol. Cell. Biol.,
April 1, 2006;
26(7):
2746 - 2757.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Jomary, J. Cullen, and S. E. Jones
Inactivation of the Akt Survival Pathway during Photoreceptor Apoptosis in the Retinal Degeneration Mouse.
Invest. Ophthalmol. Vis. Sci.,
April 1, 2006;
47(4):
1620 - 1629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Pierchala, J. Milbrandt, and E. M. Johnson Jr
Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation.
J. Neurosci.,
March 8, 2006;
26(10):
2777 - 2787.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Read, P. J. Goodfellow, E. R. Mardis, N. Novak, J. R. Armstrong, and R. L. Cagan
A Drosophila Model of Multiple Endocrine Neoplasia Type 2
Genetics,
November 1, 2005;
171(3):
1057 - 1081.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-C. Liou, S.-Y. Ho, M.-R. Shen, Y.-P. Liao, W.-T. Chiu, and K.-H. Kang
A rapid, nongenomic pathway facilitates the synaptic transmission induced by retinoic acid at the developing synapse
J. Cell Sci.,
October 15, 2005;
118(20):
4721 - 4730.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. K. Jackson, L. Gao, and C. Zhu
Mechanism of the Vascular Angiotensin II/{alpha}2-Adrenoceptor Interaction
J. Pharmacol. Exp. Ther.,
September 1, 2005;
314(3):
1109 - 1116.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Xie, P. A. Singleton, L. Y.W. Bourguignon, and D. D. Bikle
Calcium-induced Human Keratinocyte Differentiation Requires src- and fyn-mediated Phosphatidylinositol 3-Kinase-dependent Activation of Phospholipase C-{gamma}1
Mol. Biol. Cell,
July 1, 2005;
16(7):
3236 - 3246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q.-L. Cui, W.-H. Zheng, R. Quirion, and G. Almazan
Inhibition of Src-like Kinases Reveals Akt-dependent and -independent Pathways in Insulin-like Growth Factor I-mediated Oligodendrocyte Progenitor Survival
J. Biol. Chem.,
March 11, 2005;
280(10):
8918 - 8928.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Crowder, H. Enomoto, M. Yang, E. M. Johnson Jr., and J. Milbrandt
Dok-6, a Novel p62 Dok Family Member, Promotes Ret-mediated Neurite Outgrowth
J. Biol. Chem.,
October 1, 2004;
279(40):
42072 - 42081.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jijiwa, T. Fukuda, K. Kawai, A. Nakamura, K. Kurokawa, Y. Murakumo, M. Ichihara, and M. Takahashi
A Targeting Mutation of Tyrosine 1062 in Ret Causes a Marked Decrease of Enteric Neurons and Renal Hypoplasia
Mol. Cell. Biol.,
September 15, 2004;
24(18):
8026 - 8036.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Liu, J. Falola, X. Zhu, Y. Gu, L. T. Kim, G. A. Sarosi, T. Anthony, and F. E. Nwariaku
Antiproliferative Effects of Src Inhibition on Medullary Thyroid Cancer
J. Clin. Endocrinol. Metab.,
July 1, 2004;
89(7):
3503 - 3509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Duxbury, H. Ito, S. W. Ashley, and E. E. Whang
CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells
J. Biol. Chem.,
May 28, 2004;
279(22):
23176 - 23182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Encinas, R. J. Crowder, J. Milbrandt, and E. M. Johnson Jr.
Tyrosine 981, a Novel Ret Autophosphorylation Site, Binds c-Src to Mediate Neuronal Survival
J. Biol. Chem.,
April 30, 2004;
279(18):
18262 - 18269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Decker and C. ffrench-Constant
Lipid Rafts and Integrin Activation Regulate Oligodendrocyte Survival
J. Neurosci.,
April 14, 2004;
24(15):
3816 - 3825.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kawamoto, K. Takeda, Y. Okuno, Y. Yamakawa, Y. Ito, R. Taguchi, M. Kato, H. Suzuki, M. Takahashi, and I. Nakashima
Identification of RET Autophosphorylation Sites by Mass Spectrometry
J. Biol. Chem.,
April 2, 2004;
279(14):
14213 - 14224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Jomary, R. M. Darrow, P. Wong, D. T. Organisciak, and S. E. Jones
Expression of Neurturin, Glial Cell Line-Derived Neurotrophic Factor, and Their Receptor Components in Light-Induced Retinal Degeneration
Invest. Ophthalmol. Vis. Sci.,
April 1, 2004;
45(4):
1240 - 1246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Wilkins, H. Majed, R. Layfield, A. Compston, and S. Chandran
Oligodendrocytes Promote Neuronal Survival and Axonal Length by Distinct Intracellular Mechanisms: A Novel Role for Oligodendrocyte-Derived Glial Cell Line-Derived Neurotrophic Factor
J. Neurosci.,
June 15, 2003;
23(12):
4967 - 4974.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Subramaniam, J. Strelau, and K. Unsicker
Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways
J. Biol. Chem.,
March 7, 2003;
278(11):
8904 - 8912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Martin-Caraballo and S. E. Dryer
Glial Cell Line-Derived Neurotrophic Factor and Target-Dependent Regulation of Large-Conductance KCa Channels in Developing Chick Lumbar Motoneurons
J. Neurosci.,
December 1, 2002;
22(23):
10201 - 10208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pedram, M. Razandi, and E. R. Levin
Deciphering Vascular Endothelial Cell Growth Factor/Vascular Permeability Factor Signaling to Vascular Permeability. INHIBITION BY ATRIAL NATRIURETIC PEPTIDE
J. Biol. Chem.,
November 8, 2002;
277(46):
44385 - 44398.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. M. Morel, C. C. Park, K. Zhu, P. Kumar, J. H. Ruth, and A. E. Koch
Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression
J. Biol. Chem.,
September 13, 2002;
277(38):
34679 - 34691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Tomac, A. D. Agulnick, N. Haughey, C.-F. Chang, Y. Zhang, C. Backman, M. Morales, M. P. Mattson, Y. Wang, H. Westphal, et al.
Effects of cerebral ischemia in mice deficient in Persephin
PNAS,
July 9, 2002;
99(14):
9521 - 9526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kato, K. Takeda, Y. Kawamoto, T. Iwashita, A. A. Akhand, T. Senga, M. Yamamoto, G. Sobue, M. Hamaguchi, M. Takahashi, et al.
Repair by Src Kinase of Function-impaired RET with Multiple Endocrine Neoplasia Type 2A Mutation with Substitutions of Tyrosines in the COOH-Terminal Kinase Domain for Phenylalanine
Cancer Res.,
April 1, 2002;
62(8):
2414 - 2422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Harris, M. Deshmukh, B. Tsui-Pierchala, A. C. Maroney, and E. M. Johnson Jr
Inhibition of the c-Jun N-Terminal Kinase Signaling Pathway by the Mixed Lineage Kinase Inhibitor CEP-1347 (KT7515) Preserves Metabolism and Growth of Trophic Factor-Deprived Neurons
J. Neurosci.,
January 1, 2002;
22(1):
103 - 113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Enomoto, P. A. Crawford, A. Gorodinsky, R. O. Heuckeroth, E. M. Johnson Jr., and J. Milbrandt
RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons
Development,
October 15, 2001;
128(20):
3963 - 3974.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
