GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
We report the expression cloning and characterization of GDNFR-alpha, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line-derived neurotrophic factor (GDNF). GDNFR-alpha binds GDNF specifically and mediates activation of the Ret protein-tyrosine kinase (PTK). Treatment of Neuro-2a cells expressing GDNFR-alpha with GDNF rapidly stimulates Ret autophosphorylation. Ret is also activated by treatment with a combination of GDNF and soluble GDNFR-alpha in cells lacking GDNFR-alpha, and this effect is blocked by a soluble Ret-Fc fusion protein. Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons, a cell type that responds to GDNF in vivo. A model for the stepwise formation of a GDNF signal-transducing complex including GDNF, GDNFR-alpha, and the Ret PTK is proposed.
Jing
S
S
Department of Immunology, Amgen,Inc., Thousand Oaks, California 91320, USA.
Wen
D
D
Yu
Y
Y
Holst
P L
PL
Luo
Y
Y
Fang
M
M
Tamir
R
R
Antonio
L
L
Hu
Z
Z
Cupples
R
R
Louis
J C
JC
Hu
S
S
Altrock
B W
BW
Fox
G M
GM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured / Q000187:drug effects; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D005333:Fetus / Q000166:cytology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D012160:Retina / Q000166:cytology; D013116:Spinal Cord / Q000166:cytology; D014443:Tyrosine / Q000378:metabolism
D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D014443:Tyrosine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat