Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells.
We have exploited a battery of approaches to address several controversies that have accompanied the expansion of the nerve growth factor (NGF) family of neurotrophic factors and the identification of the Trk tyrosine kinases as receptors for these factors. For example, we find that a recently cloned mammalian neurotrophin, known as either neurotrophin-4 or neurotrophin-5 and assigned widely differing receptor specificities, represents the functional counterpart of Xenopus neurotrophin-4 and is a "preferred" ligand for TrkB. However, its interactions with TrkB can be distinguished from those of brain-derived neurotrophic factor (BDNF) with TrkB. We also find that all of the Trks display similar dose responses to their "preferred" ligands in neuronal as compared with nonneuronal cells (i.e., NGF for TrkA, BDNF and NT-4/5 for TrkB, and NT-3 for TrkC), providing evidence against a role for accessory molecules expressed in neurons in generating receptors that would allow for responses to lower concentrations of the neurotrophins. However, we find that a neuronal environment does restrict the Trks in their ability to respond to their "nonpreferred" neurotrophin ligands.
Ip
Nancy Y
NY
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591.
Stitt
Trevor N
TN
Tapley
Peter
P
Klein
Rudiger
R
Glass
David J
DJ
Fandl
James
J
Greene
Lloyd A
LA
Barbacid
Mariano
M
Yancopoulos
George D
GD
D016475:3T3 Cells; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D020801:Receptor, Ciliary Neurotrophic Factor; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; C071951:neurotrophin 5; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C073922:neurotrophin 4