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Regulation of neuronal nitric-oxide synthase activity by somatostatin analogs following SST5 somatostatin receptor activation.

Abstract
Somatostatin receptor SST5 is an inhibitory G protein-coupled receptor that exerts a strong cytostatic effect on various cell types. We reported previously that the SST5 anti-proliferative effect results in the inhibition of mitogen-induced increases in intracellular cGMP levels and MAPK activity. This study was conducted to define the early molecular events accountable for the SST5-mediated anti-proliferative effect. Here, we demonstrate that, in Chinese hamster ovary cells expressing SST5 (CHO/SST5 cells), somatostatin inhibited cell proliferation induced by nitric oxide donors and overexpression of the neuronal nitric-oxide synthase (nNOS) protein isoform. Accordingly, nNOS activity and dimerization were strongly inhibited following SST5 activation by the somatostatin analog RC-160. In CHO/SST5 cells, nNOS was dynamically recruited by the SST5 receptor and phosphorylated at tyrosyl residues following RC-160 treatment. RC-160 induced SST5-p60(src) kinase complex formation and subsequent p60(src) kinase activation. Coexpression of an inactive p60(src) kinase mutant with SST5 blocked RC-160-induced nNOS phosphorylation and inactivation and prevented the SST5-mediated anti-proliferative effect. In CHO/SST5 cells, p60(src) kinase associated with nNOS to induce its inactivation by phosphorylation at tyrosyl residues following RC-160 treatment. Using recombinant proteins, we demonstrated that such phosphorylation prevented nNOS homodimerization. Next, surface plasmon resonance and mutation analysis revealed that p60(src) directly associated with nNOS phosphorylated Tyr604. SST5-mediated inhibition of nNOS activity was demonstrated to be essential to the RC-160 anti-proliferative effect on pancreatic endocrine tumor-derived cells. We therefore identified nNOS as a new p60(src) kinase substrate essential for SST5-mediated anti-proliferative action.
AuthorsPierre Cordelier, Jean-Pierre Estève, Souad Najib, Luis Moroder, Nicole Vaysse, Lucien Pradayrol, Christiane Susini, Louis Buscail
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 28 Pg. 19156-71 (Jul 14 2006) ISSN: 0021-9258 [Print] United States
PMID16690617 (Publication Type: Journal Article)
Chemical References
  • Protein Isoforms
  • Receptors, Somatostatin
  • Recombinant Proteins
  • somatostatin receptor 5
  • Somatostatin
  • Nitric Oxide Synthase Type I
  • Proto-Oncogene Proteins pp60(c-src)
Topics
  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cell Proliferation
  • Cricetinae
  • Dimerization
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Nitric Oxide Synthase Type I (metabolism)
  • Phosphorylation
  • Protein Isoforms
  • Proto-Oncogene Proteins pp60(c-src) (chemistry)
  • Rats
  • Receptors, Somatostatin (metabolism)
  • Recombinant Proteins
  • Somatostatin (analogs & derivatives)

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