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PACAP type I receptor transactivation is essential for IGF‐1 receptor signalling and antiapoptotic activity in neurons
Author(s) -
Delcourt Nicolas,
Thouvenot Eric,
Chanrion Benjamin,
Galéotti Nathalie,
Jouin Patrick,
Bockaert Joël,
Marin Philippe
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601608
Subject(s) - biology , transactivation , receptor , signalling , signal transduction , microbiology and biotechnology , endocrinology , medicine , genetics , transcription factor , gene
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.