title: Identification of human somatostatin receptor 2 domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line.
abstract: Somatostatin exerts inhibitory effects on hormone secretion and cell proliferation via five receptor subtypes (SST1-SST5), whose internalization is regulated by β-arrestins. The receptor domains involved in these effects have been only partially elucidated. The aim of the study is to characterize the molecular mechanism and determinants responsible for somatostatin receptor 2 internalization and signaling in pancreatic neuroendocrine QGP-1 cell line, focusing on the third intracellular loop and carboxyl terminal domains. We demonstrated that in cells transfected with somatostatin receptor 2 third intracellular loop mutant, no differences in β-arrestins recruitment and receptor internalization were observed after somatostatin receptor 2 activation in comparison with cells bearing wild-type somatostatin receptor 2. Conversely, the truncated somatostatin receptor 2 failed to recruit β-arrestins and to internalize after somatostatin receptor 2 agonist (BIM23120) incubation. Moreover, the inhibitory effect of BIM23120 on cell proliferation, cyclin D1 expression, P-ERK1/2 levels, apoptosis and vascular endothelial growth factor secretion was completely lost in cells transfected with either third intracellular loop or carboxyl terminal mutants. In conclusion, we demonstrated that somatostatin receptor 2 internalization requires intact carboxyl terminal while the effects of SS on cell proliferation, angiogenesis and apoptosis mediated by somatostatin receptor 2 need the integrity of both third intracellular loop and carboxyl terminal.
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cambiaghi
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vitali
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Morone
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Peverelli
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.affiliation: Endocrine Unit, Humanitas Clinical and Research Center, Rozzano, Italy. andrea.lania@humanitas.it.|Humanitas University, School of Medicine, Rozzano, Italy. andrea.lania@humanitas.it.
authors.forename: Andrea Gerardo
authors.initials: AG
authors.lastname: Lania
mesh_terms: D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D017481:Receptors, Somatostatin; D042461:Vascular Endothelial Growth Factor A; D000071557:beta-Arrestins; C093733:somatostatin receptor 2; D053148:Caspase 3
keywords: Somatostatin 2 receptor subtype; Somatostatin receptor; pancreatic neuroendocrine tumors; β-arrestins