View the Current Issue

Article

  • The EMBO Journal (2007) 26, 1542 - 1551
  • doi:10.1038/sj.emboj.7601608

Published online: 1 March 2007

PACAP type I receptor transactivation is essential for IGF-1 receptor signalling and antiapoptotic activity in neurons

Nicolas Delcourt1,2,3,4,5, Eric Thouvenot1,2,3,4,5, Benjamin Chanrion1,2,3,4,5, Nathalie Galéotti1,2,3,4,5, Patrick Jouin1,2,3,4,5, Joël Bockaert1,2,3,4,5 and Philippe Marin1,2,3,4,5

  1. CNRS UMR 5203, Montpellier, France
  2. INSERM, U661, Montpellier, France
  3. University Montpellier I, Montpellier, France
  4. University Montpellier II, Montpellier, France
  5. Département de Neurobiologie, Institut de Génomique Fonctionnelle, Montpellier, France

Correspondence to:

Joël Bockaert, Département de Neurobiologie, Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France. Tel.: +33 467 14 29 30; Fax: +33 467 14 29 10; E-mail: joel.bockaert@igf.cnrs.fr

Received 7 September 2006; Accepted 24 January 2007

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.

  • Keywords:

    • apoptosis,
    • IGF-1,
    • PACAP,
    • phosphoproteome,
    • transactivation