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  • The EMBO Journal (2006) 25, 3943 - 3954
  • doi:10.1038/sj.emboj.7601279

Published online: 17 August 2006

Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway

Corinne Bousquet1,4, Julie Guillermet-Guibert1,4, Nathalie Saint-Laurent1, Elodie Archer-Lahlou1, Frédéric Lopez2, Marjorie Fanjul1, Audrey Ferrand1, Daniel Fourmy1, Carole Pichereaux3, Bernard Monsarrat3, Lucien Pradayrol1, Jean-Pierre Estève1 and Christiane Susini1

  1. INSERM U531, Institut Louis Bugnard, CHU Rangueil, Toulouse cedex 4, France
  2. IFR 31, Institut Louis Bugnard, CHU Rangueil, Toulouse cedex 4, France
  3. Institut de Pharmacologie et de Biologie Structurale, CNRS, Toulouse cedex, France
  4. These authors contributed equally to this work

Correspondence to:

Corinne Bousquet, INSERM U531, IFR31, Institut Louis Bugnard, BP 84225, CHU Rangueil, 31432 Toulouse cedex 4, France. Tel.: +33 5 61 32 24 07; Fax: +33 5 61 32 24 03; E-mail: Corinne.Bousquet@toulouse.inserm.fr.

Received 11 November 2005; Accepted 21 July 2006

Phosphatidylinositol 3-kinase (PI3K) regulates many cellular functions including growth and survival, and its excessive activation is a hallmark of cancer. Somatostatin, acting through its G protein-coupled receptor (GPCR) sst2, has potent proapoptotic and anti-invasive activities on normal and cancer cells. Here, we report a novel mechanism for inhibiting PI3K activity. Somatostatin, acting through sst2, inhibits PI3K activity by disrupting a pre-existing complex comprising the sst2 receptor and the p85 PI3K regulatory subunit. Surface plasmon resonance and molecular modeling identified the phosphorylated-Y71 residue of a p85-binding pYXXM motif in the first sst2 intracellular loop, and p85 COOH-terminal SH2 as direct interacting domains. Somatostatin-mediated dissociation of this complex as well as p85 tyrosine dephosphorylation correlates with sst2 tyrosine dephosphorylation on the Y71 residue. Mutating sst2-Y71 disabled sst2 to interact with p85 and somatostatin to inhibit PI3K, consequently abrogating sst2's ability to suppress cell survival and tumor growth. These results provide the first demonstration of a physical interaction between a GPCR and p85, revealing a novel mechanism for negative regulation by ligand-activated GPCR of PI3K-dependent survival pathways, which may be an important molecular target for antineoplastic therapy.

  • Keywords:

    • cell survival,
    • G protein-coupled sst2 somatostatin receptor,
    • PI3K pathway,
    • protein interaction,
    • tumor growth