PACAP type I receptor transactivation is essential for IGF-1 receptor signalling and antiapoptotic activity in neurons.
Insulin-like growth factor-1 (IGF-1) and pituitary adenylyl cyclase activating polypeptide (PACAP) are both potent neurotrophic and antiapoptotic factors, which exert their effects via phosphorylation cascades initiated by tyrosine kinase and G-protein-coupled receptors, respectively. Here, we have adapted a recently described phosphoproteomic approach to neuronal cultures to characterize the phosphoproteomes generated by these neurotrophic factors. Unexpectedly, IGF-1 and PACAP increased the phosphorylation state of a common set of proteins in neurons. Using PACAP type 1 receptor (PAC1R) null mice, we showed that IGF-1 transactivated PAC1Rs constitutively associated with IGF-1 receptors. This effect was mediated by Src family kinases, which induced PAC1R phosphorylation on tyrosine residues. PAC1R transactivation was responsible for a large fraction of the IGF-1-associated phosphoproteome and played a critical role in the antiapoptotic activity of IGF-1. Hence, in contrast to the general opinion that the trophic activity of IGF-1 is solely mediated by tyrosine kinase receptor-associated signalling, we show that it involves a more complex signalling network dependent on the PAC1 Gs-protein-coupled receptor in neurons.
Delcourt
Nicolas
N
CNRS UMR 5203, Montpellier, France.
Thouvenot
Eric
E
Chanrion
Benjamin
B
Galéotti
Nathalie
N
Jouin
Patrick
P
Bockaert
Joël
J
Marin
Philippe
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015533:Transcriptional Activation / Q000502:physiology*
D007457:Iodine Radioisotopes; D010750:Phosphoproteins; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP