ArticleThe EMBO journal2006
Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway.
Article in The EMBO journal, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 84 citations in OpenAlex.
- Review
- Beneath the surface: endosomal GPCR signaling.Trends in biochemical sciences · 2024Review
- Selective somatostatin receptor 5 inhibition improves hepatic insulin sensitivity.Pharmacology research & perspectives · 2023Article
- Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.EMBO molecular medicine · 2021Article
- β-Ionone Attenuates Dexamethasone-Induced Suppression of Collagen and Hyaluronic Acid Synthesis in Human Dermal Fibroblasts.Biomolecules · 2021Article
- SSTR2 is a prognostic factor and a promising therapeutic target in glioma.American journal of translational research · 2021Article
- Article
- Clinical Significance of Somatostatin Receptor (SSTR) 2 in Meningioma.Frontiers in oncology · 2020Review
- p85α Inactivates MMP-2 and Suppresses Bladder Cancer Invasion by Inhibiting MMP-14 Transcription and TIMP-2 Degradation.Neoplasia (New York, N.Y.) · 2019Article
- International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.Pharmacological reviews · 2018Review
- Article
- Article
- Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy.Scientific reports · 2017Article
- Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts.Oncotarget · 2016Article
- Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- High constitutive Akt2 activity in U937 promonocytes: effective reduction of Akt2 phosphorylation by the histamine H2-receptor and the β2-adrenergic receptor.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas.Journal of neuro-oncology · 2015Article
- Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance.EMBO molecular medicine · 2015Article
- The expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors.Drugs · 2015Review
- KIM-1-mediated phagocytosis reduces acute injury to the kidney.The Journal of clinical investigation · 2015Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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