14-3-3 proteins regulate protein kinase a activity to modulate growth cone turning responses.
Growth cones regulate the speed and direction of neuronal outgrowth during development and regeneration. How the growth cone spatially and temporally regulates signals from guidance cues is poorly understood. Through a proteomic analysis of purified growth cones we identified isoforms of the 14-3-3 family of adaptor proteins as major constituents of the growth cone. Disruption of 14-3-3 via the R18 antagonist or knockdown of individual 14-3-3 isoforms switches nerve growth factor- and myelin-associated glycoprotein-dependent repulsion to attraction in embryonic day 13 chick and postnatal day 5 rat DRG neurons. These effects are reminiscent of switching responses observed in response to elevated cAMP. Intriguingly, R18-dependent switching is blocked by inhibitors of protein kinase A (PKA), suggesting that 14-3-3 proteins regulate PKA. Consistently, 14-3-3 proteins interact with PKA and R18 activates PKA by dissociating its regulatory and catalytic subunits. Thus, 14-3-3 heterodimers regulate the PKA holoenzyme and this activity plays a critical role in modulating neuronal responses to repellent cues.
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Christopher B
CB
Kent
Tadayuki
T
Shimada
Gino B
GB
Ferraro
Brigitte
B
Ritter
Patricia T
PT
Yam
Peter S
PS
McPherson
Frédéric
F
Charron
Timothy E
TE
Kennedy
Alyson E
AE
Fournier
D048948:14-3-3 Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002642:Chick Embryo; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D020439:Growth Cones / Q000502:physiology*; D047468:Immunoprecipitation; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048948:14-3-3 Proteins; D018992:Myelin-Associated Glycoprotein; D020932:Nerve Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases