Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway.
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.
Bousquet
Corinne
C
INSERM U531, Institut Louis Bugnard, CHU Rangueil, Toulouse cedex 4, France. Corinne.Bousquet@toulouse.inserm.fr
Guillermet-Guibert
Julie
J
Saint-Laurent
Nathalie
N
Archer-Lahlou
Elodie
E
Lopez
Frédéric
F
Fanjul
Marjorie
M
Ferrand
Audrey
A
Fourmy
Daniel
D
Pichereaux
Carole
C
Monsarrat
Bernard
B
Pradayrol
Lucien
L
Estève
Jean-Pierre
JP
Susini
Christiane
C
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
D017481:Receptors, Somatostatin; D014443:Tyrosine; D013004:Somatostatin; C093733:somatostatin receptor 2; D019869:Phosphatidylinositol 3-Kinases