Somatostatin Activation of Mitogen-Activated Protein Kinase via Somatostatin Receptor 1 (SSTR1)

Florio, Tullio; Hong, Ying; Carey, Kendall D.; Dillon, Tara J.; Stork, Philip J.S.

doi:10.1210/mend.13.1.0224

Cited by 107 publications

(110 citation statements)

References 87 publications

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“…First, agonist binding to the sst1 receptor is completely resistant to GTP inhibition after pertussis toxin treatment of CHO-K1 cells (17). Second, all sst1-mediated signaling in CHO-K1 cells, including cyclase inhibition, inositol 1,4,5-trisphosphate formation, tyrosine phosphatase stimulation, and mitogen-activated protein kinase activation are blocked by pertussis toxin (15,20,44). Together, these observations provide strong support for the conclusion that the sst1 receptor is coupled exclusively to pertussis toxin-sensitive G proteins in this cell line.…”

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confidence: 99%

Agonist-induced Phosphorylation of Somatostatin Receptor Subtype 1 (Sst1)

Liu

Schönbrunn

2001

Journal of Biological Chemistry

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The sst1 somatostatin (SRIF) receptor subtype is widely expressed in the endocrine, gastrointestinal, and neuronal systems as well as in hormone-sensitive tumors, yet little is known about its regulation. Here we investigated the desensitization, internalization, and phosphorylation of sst1 expressed in CHO-K1 cells. Treatment of cells with 100 nM SRIF for 30 min reduced maximal SRIF inhibition of adenylyl cyclase from 40 to 10%. This desensitization was rapid (t1 ⁄2 < 2 min) and dependent on agonist concentration (EC 50 ‫؍‬ 2 nM). However, internalization of receptor-bound ligand occurred slowly (t1 ⁄2 > 180 min). Incubation of cells with SRIF also caused a rapid (t1 ⁄2 < 2 min) increase in sst1 receptor phosphorylation in a dose-dependent manner (EC 50 ‫؍‬ 1.3 nM), as determined in a mobility shift phosphorylation assay. Receptor phosphorylation was not affected by pertussis toxin, indicating a requirement for receptor occupancy rather than signaling. The protein kinase C activator, phorbol 12-myristate 13-acetate also stimulated sst1 receptor phosphorylation whereas forskolin did not. Both agonist-and phorbol 12-myristate 13-acetate-stimulated receptor phosphorylation occurred mainly on serine. These studies are the first to demonstrate phosphorylation of the sst1 receptor and suggest that phosphorylation mediated uncoupling, rather than sequestration, leads to its desensitization.The two physiologically active somatostatin (SRIF) 1 peptides, SRIF14 and SRIF28, potently regulate numerous endocrine, exocrine, and neuronal functions by interacting with a family of six G protein-coupled receptors (sst1, sst2A, sst2B, sst3, sst4, and sst5) (1-4). The cellular changes induced by sst receptors include inhibition of secretion, modulation of neuronal transmission, and smooth muscle contraction, as well as inhibition of proliferation and stimulation of apoptosis. The sst1 receptor subtype is particularly widely distributed in the gastrointestinal tract (5, 6) and the brain (7, 8) as well as being expressed in several other normal tissues (9, 10). Additionally, sst1 is found in neuroendocrine, prostate, and mammary tumors (11-13). Thus, this receptor subtype is believed to mediate many of the central and peripheral actions of SRIF as well as to present a potential target for cancer therapy and diagnosis (1-4, 14).The sst1 receptor, like other members of the somatostatin receptor family, is now known to inhibit adenylyl cyclase by interacting with pertussis toxin-sensitive G i /G o proteins (15-17). Other signaling mechanisms potently regulated by the sst1 receptor in a pertussis toxin-sensitive manner include inhibition of Ca 2ϩ influx, membrane hyperpolarization, activation of protein tyrosine phosphatases, and stimulation of the mitogenactivated protein kinase cascade (18 -20). However, the sst1 receptor has also been shown to act via pertussis toxin-insensitive mechanisms. Both activation of Na ϩ /H ϩ exchange and potentiation of ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate current responses to gluta...

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confidence: 99%

Agonist-induced Phosphorylation of Somatostatin Receptor Subtype 1 (Sst1)

Liu

Schönbrunn

2001

Journal of Biological Chemistry

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“…There are six SS receptors, all of which are G-protein coupled receptors (GPCRs) (3,4), which couple through G i/o . SS transduces its physiological signal through many effectors, which include adenylyl cyclase (5), inwardly rectifying K ϩ channels (6), tyrosine phosphatase (7), phospholipase C (8), voltage-dependent Ca 2ϩ channel (9), Na ϩ -H ϩ antiporter (10), and mitogen-activated protein kinase (11). We recently reported that SS can activate phospholipase D (PLD), causing a subsequent increase in phosphoinositol 4,5-bisphosphate (PIP 2 ) concentration (12).…”

Section: Somatostatin (Ss)mentioning

confidence: 99%

“…Both PKC isoforms are known to enhance the activity of PLD. GPCR activation of small G-proteins can be involved in stimulating PLD (6,11). The signaling mechanisms responsible for small G-protein regulation of PLD are diverse, but two small G-proteins, Rho and Arf, have been firmly established to regulate PLD activity through GPCRs (26,(32)(33)(34)(35)(36).…”

Section: Somatostatin (Ss)mentioning

confidence: 99%

Somatostatin Receptors Signal through EFA6A-ARF6 to Activate Phospholipase D in Clonal β-Cells

Grodnitzky

Syed

Kimber

et al. 2007

Journal of Biological Chemistry

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Somatostatin (SS) is a peptide hormone that inhibits insulin secretion inThese findings suggested that Arf6, but not Arf1 or Arf5, mediates the effect of SS. We further determined the involvement of the Arf6 guanine nucleotide exchange factor (GEF) EFA6A, a GEF previously thought to be found predominantly in the brain, in the activation of PLD1 in HIT-T15 cells. Using Northern and Western blot analyses, both mRNA and protein of EFA6A were found in these cells. Overexpression of dn-EFA6A mutant, EFA6A(E242K), and suppression of mRNA levels using siRNA, both abolished SS-induced PLD activation, whereas overexpression of dn-EFA6B mutant, EFA6B(E651K), failed to reduce SS-induced PLD activation. In addition, overexpression of dn-ARNO mutant, ARNO(E156K), another GEF of Arf6, had no effect on SS-induced activation of PLD. Taken together, these results suggest that SS signals through EFA6A to activate Arf6-PLD cascade.

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“…[11] The direct mode of action involves interaction with somatostatin receptors on tumor cells leading to activation of phosphotyrosine phosphatases [12] and modulation of the mitogen-activated protein kinase signaling pathway. [13] The indirect antiproliferative effect occurs through inhibition of expression of growth factors, such as insulin-like growth factor and vascular endothelial growth factor. [14] Activities of SSAs are mediated by interaction of somatostatin with a series of five receptors (SSTRs) encoded by five different genes belonging to the class of receptors linked to transmembrane G-proteins, able to inhibit cAMP.…”

Section: Introductionmentioning

confidence: 99%

Review of recents advances in medical treatment for neuroendocrine neoplasms: somatostatin analogs and chemotherapy

Spada¹,

Valente²

2016

JCMT

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Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms. There are a number of different types of NENs. They usually arise as advanced and low/intermediate grade only in a minority of cases, as high grade. Treatment depends on which type and may include surgery, interventional radiology, and systemic treatment, including chemotherapy, somatostatin analogs, interferon α2b, peptide receptor radionuclide therapy, and only for pancreatic neuroendocrine tumors, molecular targeted agents, including everolimus and sunitinib. The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy. The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features, such as symptoms and endocrine markers.

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Somatostatin Activation of Mitogen-Activated Protein Kinase via Somatostatin Receptor 1 (SSTR1)

Cited by 107 publications

References 87 publications

Agonist-induced Phosphorylation of Somatostatin Receptor Subtype 1 (Sst1)

Agonist-induced Phosphorylation of Somatostatin Receptor Subtype 1 (Sst1)

Somatostatin Receptors Signal through EFA6A-ARF6 to Activate Phospholipase D in Clonal β-Cells

Review of recents advances in medical treatment for neuroendocrine neoplasms: somatostatin analogs and chemotherapy

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