title: Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway.
abstract: 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.
authors.affiliation: INSERM U531, Institut Louis Bugnard, CHU Rangueil, Toulouse cedex 4, France. Corinne.Bousquet@toulouse.inserm.fr
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saint-Laurent
authors.forename: Elodie
authors.initials: E
authors.lastname: Archer-Lahlou
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lopez
authors.forename: Marjorie
authors.initials: M
authors.lastname: Fanjul
authors.forename: Audrey
authors.initials: A
authors.lastname: Ferrand
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
authors.forename: Carole
authors.initials: C
authors.lastname: Pichereaux
authors.forename: Bernard
authors.initials: B
authors.lastname: Monsarrat
authors.forename: Lucien
authors.initials: L
authors.lastname: Pradayrol
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Estève
authors.forename: Christiane
authors.initials: C
authors.lastname: Susini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D017481:Receptors, Somatostatin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013004:Somatostatin / Q000502:physiology*; D020349:Surface Plasmon Resonance; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D017481:Receptors, Somatostatin; D014443:Tyrosine; D013004:Somatostatin; C093733:somatostatin receptor 2; D019869:Phosphatidylinositol 3-Kinases