Heterodimeric neurotrophins induce phosphorylation of Trk receptors and promote neuronal differentiation in PC12 cells.
Neurotrophins are a family of highly conserved proteins that affect the development and maintenance of distinct neuronal populations. Neurotrophins exist in vivo as homodimers, but we show that neurotrophins can exist as heterodimers in vitro and are pluripotent, being able to bind and to activate different Trk tyrosine kinase receptors as well as promote neuronal differentiation in PC12 cells as effectively as wild type homodimers. These asymmetric neurotrophin dimers allow unique characterization of neurotrophin structure-function relationships with Trk receptors. The chimeric Trk activities of these heterodimers suggest an alternative model of neurotrophin-Trk receptor activation in which the critical Trk-interacting elements may be attributed to a single protomer.
Treanor
J J
JJ
Department of Neuroscience, Genentech, Incorporated, South San Francisco, California 94080-4990, USA.
Schmelzer
C
C
Knusel
B
B
Winslow
J W
JW
Shelton
D L
DL
Hefti
F
F
Nikolics
K
K
Burton
L E
LE
D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects*; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008961:Models, Structural; D009414:Nerve Growth Factors / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
D046911:Macromolecular Substances; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA