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J. Biol. Chem., Vol. 277, Issue 3, 1991-1999, January 18, 2002
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From the Division of Molecular Neurobiology, Department of
Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden
The catalytic and signaling
activities of RET, a tyrosine kinase receptor for glial cell
line-derived neurotrophic factor (GDNF), are controlled by the
autophosphorylation of several tyrosine residues in the RET cytoplasmic
domain. To analyze the phosphorylation state of individual tyrosines,
we generated antibodies recognizing specific phosphotyrosine sites
involved in the catalytic (Tyr905) and downstream
signaling (Tyr1015, Tyr1062, and
Tyr1096) activities of this receptor. Stimulation with GDNF
induced coordinated phosphorylation of the 4 tyrosine residues in
neuronal cell lines and in primary cultures of sympathetic neurons
isolated from rat superior cervical ganglia. Neurturin and
artemin, two other members of the GDNF ligand family, also induced
synchronized phosphorylation of RET tyrosines with kinetics comparable
to those observed with GDNF. Tyrosine phosphorylation was maximal 15 min after ligand stimulation, decaying thereafter with similar kinetics
in all 4 residues. Co-stimulation with a soluble form of the GFR
Coordinated Activation of Autophosphorylation Sites in the RET
Receptor Tyrosine Kinase
IMPORTANCE OF TYROSINE 1062 FOR GDNF MEDIATED NEURONAL
DIFFERENTIATION AND SURVIVAL*
,
1
co-receptor potentiated ligand-dependent phosphorylation of
different intracellular tyrosines to a similar extent and increased the
survival of superior cervical ganglion neurons compared with treatment
with GDNF alone. In vivo, high levels of phosphorylated
Tyr905, Tyr1015, and Tyr1062 were
detected in embryonic mouse dorsal root ganglia, with a sharp decline
at early postnatal stages. Protein transduction of
anti-Tyr(P)1062 antibodies into cultured cells
reduced activation of MAPKs ERK1 and ERK2 and the AKT
kinase in response to GDNF and diminished GDNF-dependent
neuronal differentiation and survival of embryonic sensory neurons from
the nodose ganglion. These results demonstrate synchronized utilization
of individual RET tyrosine residues in neurons in vivo and
reveal an important role for RET Tyr1062 in mediating
neuronal survival by GDNF.
*
This work was supported in part by Grant 3474-B97-05XBC from
the Swedish Cancer Society, Grant QLRT-1999-00099 from the Fifth Framework Program of the European Commission, the Göran
Gustafssons Stiftelse, and the Karolinska Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported in part by grants from the Swedish Medical Research
Council and the Swedish Cancer Society.
§
Supported in part by Grant An 338/1-1 from the Deutsche
Forschungsgemeinschaft (Bonn, Germany).
¶
To whom correspondence should be addressed: Div. of Molecular
Neurobiology, Dept. of Neuroscience, Karolinska Inst., Retzius väg 8 A2:2, S-171 77 Stockholm, Sweden. Tel.: 46-8-728-7660; Fax:
46-8-33-9548; E-mail: carlos.ibanez@neuro.ki.se.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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