Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Bousquet, C. et al.

Bousquet, Guillermet-Guibert, Saint-Laurent, Archer-Lahlou, Lopez, Fanjul, Ferrand, Fourmy, Pichereaux, Monsarrat, Pradayrol, Estève, Susini,

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-Y(71) 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 Y(71) residue. Mutating sst2-Y(71) 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.[1]

References

Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. Bousquet, C., Guillermet-Guibert, J., Saint-Laurent, N., Archer-Lahlou, E., Lopez, F., Fanjul, M., Ferrand, A., Fourmy, D., Pichereaux, C., Monsarrat, B., Pradayrol, L., Estève, J.P., Susini, C. EMBO J. (2006) [Pubmed]

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