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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.

SUBMITTER: Bousquet C

PROVIDER: S-EPMC1560358 | biostudies-other | 2006 Sep

REPOSITORIES: biostudies-other

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

Bousquet Corinne C 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

The EMBO journal 20060817 17

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 an ...[more]

PMID: 16917505

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Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day. aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.

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

Publications

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

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