Somatostatin Receptor Type 2 (SSTR2) Internalization and
                    Intracellular Trafficking in Pituitary GH-Secreting Adenomas: Role of Scaffold
                    Proteins and Implications for Pharmacological Resistance

D. Treppiedi; E. Peverelli; E. Giardino; E. Ferrante; D. Calebiro; A. Spada; G. Mantovani

doi:10.1055/s-0042-116025

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2017; 49(04): 259-268
DOI: 10.1055/s-0042-116025

Review

Somatostatin Receptor Type 2 (SSTR2) Internalization and Intracellular Trafficking in Pituitary GH-Secreting Adenomas: Role of Scaffold Proteins and Implications for Pharmacological Resistance

Authors

D. Treppiedi^*

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
E. Peverelli^*

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
E. Giardino

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
E. Ferrante

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
D. Calebiro

²Institute of Pharmacology and Toxicology, University of Würzburg, and Rudolf Virchow Center, Bio-Imaging Center, Würzburg, Germany
A. Spada

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
G. Mantovani

¹Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Abstract

Somatostatin receptor type 2 (SSTR2), together with SSTR5, represents the main target of medical treatment for growth hormone (GH)-secreting pituitary tumors, since it is expressed in most of these tumors and exerts both antiproliferative and cytostatic effects, and reduces hormone secretion, as well. However, clinical practice indicates a great variability in the frequency and entity of favorable responses of acromegalic patients to long-acting somatostatin analogues (SSAs), but the molecular mechanisms regulating this pharmacological resistance are not completely understood. So far, several potentially implied mechanisms have been suggested, including impaired expression of SSTRs, or post-receptor signal transduction alterations. More recently, new studies exploited the molecular factors involved in SSTRs intracellular trafficking regulation, this being a critical point for the modulation of the available active G-coupled receptors (GPCRs) amount at the cell surface. In this respect, the role of the scaffold proteins such as β-arrestins, and the cytoskeleton protein Filamin A (FLNA), have become of relevant importance for GH-secreting pituitary tumors. In fact, β-arrestins are linked to SSTR2 desensitization and internalization, and FLNA is able to regulate SSTR2 trafficking and stability at the plasma membrane. Therefore, the present review will summarize emerging evidence highlighting the role of β-arrestins and FLNA, as possible novel players in the modulation of agonist activated-SSTR2 receptor trafficking and response in GH-secreting pituitary tumors.

Key words

pituitary tumors - receptor endocytosis - β-arrestins - filamin A

Full Text

References

References
1 Ben-Shlomo A, Melmed S. Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 2010; 21: 123-133
2 Buscail L, Estève JP, Saint-Laurent N, Bertrand V, Reisine T, O’Carroll AM, Bell GI, Schally AV, Vaysse N, Susini C. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci U S A 1995; 92: 1580-1584
3 Ferrante E, Pellegrini C, Bondioni S, Peverelli E, Locatelli M, Gelmini P, Luciani P, Peri A, Mantovani G, Bosari S, Beck-Peccoz P, Spada A, Lania AG. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer 2006; 13: 955-962
4 Gueorguiev M, Grossman AB. Pituitary tumors in 2010: a new therapeutic era for pituitary tumors. Nat Rev Endocrinol 2011; 7: 71-73
5 Reubi JC, Eisenwiener KP, Rink H, Waser B, Mäcke HR. A new peptidic somatostatin agonist with high affinity to all five somatostatin receptors. Eur J Pharmacol 2002; 456: 45-49
6 Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 2002; 146: 707-716
7 Oberg K. Future aspects of somatostatin-receptor-mediated therapy. Neuroendocrinology 2004; 80 (Suppl. 01) 57-61
8 Colao A, Bronstein MD, Freda P, Gu F, Shen C-C, Gadelha M, Fleseriu M, van der Lely AJ, Farrall AJ, Hermosillo Reséndiz K, Ruffin M, Chen Y, Sheppard M. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab 2014; 99: 791-799
9 Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, Pronin V, Raverot G, Shimon I, Lievre KK, Fleck J, Aout M, Pedroncelli AM, Colao A. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol 2014; 2: 875-884
10 Lamberts SW, van der Lely AJ, Hofland LJ. New somatostatin analogs: will they fulfil old promises?. Eur J Endocrinol 2002; 146: 701-705
11 Colao A, Auriemma RS, Lombardi G, Pivonello R. Resistance to somatostatin analogs in acromegaly. Endocr Rev 2011; 32: 247-271
12 Howlett TA, Willis D, Walker G, Wass JA, Trainer PJ. UK Acromegaly Register Study Group . (UKAR-3). Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists. Clin Endocrinol (Oxf) 2013; 79: 689-699
13 Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S. Acromegaly Consensus Group . A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 2010; 95: 3141-3148
14 Reubi JC, Landolt AM. The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 1989; 68: 844-850
15 Plöckinger U, Albrecht S, Mawrin C, Saeger W, Buchfelder M, Petersenn S, Schulz S. Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas. J Clin Endocrinol Metab 2008; 93: 1203-1210
16 Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, de Jong T, Minuto F, Colao A, Lamberts SW, Hofland LJ. Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 2008; 93: 1412-1417
17 Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 2013; 16: 490-498
18 Barlier A, Gunz G, Zamora AJ, Morange-Ramos I, Figarella-Branger D, Dufour H, Enjalbert A, Jaquet P. Pronostic and therapeutic consequences of Gs alpha mutations in somatotroph adenomas. J Clin Endocrinol Metab 1998; 83: 1604-1610
19 Resmini E, Dadati P, Ravetti JL, Zona G, Spaziante R, Saveanu A, Jaquet P, Culler MD, Bianchi F, Rebora A, Minuto F, Ferone D. Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient. J Clin Endocrinol Metab 2007; 92: 1592-1599
20 Peverelli E, Mantovani G, Calebiro D, Doni A, Bondioni S, Lania AG, Beck-Peccoz P, Spada A. The third intracellular loop of the human somatostatin receptor 5 is crucial for arrestin binding and receptor internalization after somatostatin stimulation. Mol Endocrinol 2008; 22: 676-688
21 Peverelli E, Giardino E, Treppiedi D, Vitali E, Cambiaghi V, Locatelli M, Lasio GB, Spada A, Lania AG, Mantovani G, Filamin A. (FLNA) plays an essential role in somatostatin receptor 2 (SST2) signaling and stabilization after agonist stimulation in human and rat somatotroph tumor cells. Endocrinology 2014; 155: 2932-2941
22 Gatto F, Feelders R, van der Pas R, Kros JM, Dogan F, van Koetsveld PM, van der Lelij AJ, Neggers SJ, Minuto F, de Herder W, Lamberts SW, Ferone D, Hofland LJ. β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. Endocrinology 2013; 154: 4715-4725
23 Gatto F, Biermasz NR, Feelders RA, Kros JM, Dogan F, Van der Lely AJ, Neggers SJ, Lamberts SW, Pereira AM, Ferone D, Hofland L. Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. Eur J Endocrinol 2016; 174: 651-662
24 Sorkin A, von Zastrow M. Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 2009; 10: 609-622
25 Luttrell LM, Gesty-Palmer D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 2010; 62: 305-330
26 Calebiro D, Nikolaev VO, Persani L, Lohse MJ. Signaling by internalized G-protein-coupled receptors. Trends Pharmacol Sci 2010; 31: 221-228
27 Reubi JC, Kappeler A, Waser B, Schonbrunn A, Laissue J. Immunohistochemical localization of somatostatin receptor sst2A in human pancreatic islets. J Clin Endocrinol Metab 1998; 83: 3746-3749
28 Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 2003; 24: 389-427
29 Körner M, Eltschinger V, Waser B, Schonbrunn A, Reubi JC. Value of immunohistochemistry for somatostatin receptor subtype sst2A in cancer tissues: lessons from the comparison of anti-sst2A antibodies with somatostatin receptor autoradiography. Am J Surg Pathol 2005; 29: 1642-1651
30 Lamberts SW, de Herder WW, Hofland LJ. Somatostatin analogs in the diagnosis and treatment of cancer. Trends Endocrinol Metab 2002; 13: 451-457
31 Patel YC, Greenwood M, Kent G, Panetta R, Srikant CB. Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation. Biochem Biophys Res Commun 1993; 192: 288-294
32 Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999; 20: 157-198
33 Tulipano G, Stumm R, Pfeiffer M, Kreienkamp HJ, Höllt V, Schulz S. Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes. J Biol Chem 2004; 279: 21374-21382
34 Liu Q, Cescato R, Dewi DA, Rivier J, Reubi JC, Schonbrunn A. Receptor signaling and endocytosis are differentially regulated by somatostatin analogs. Mol Pharmacol 2005; 68: 90-101
35 Grant M, Collier B, Kumar U. Agonist-dependent dissociation of human somatostatin receptor 2 dimers: a role in receptor trafficking. J Biol Chem 2004; 279: 36179-36183
36 Peverelli E, Mantovani G, Vitali E, Elli FM, Olgiati L, Ferrero S, Laws ER, Della Mina P, Villa A, Beck-Peccoz P, Spada A, Lania AG. Filamin-A is essential for dopamine d2 receptor expression and signaling in tumorous lactotrophs. J Clin Endocrinol Metab 2012; 97: 967-977
37 Sarret P, Esdaile MJ, McPherson PS, Schonbrunn A, Kreienkamp HJ, Beaudet A. Role of amphiphysin II in somatostatin receptor trafficking in neuroendocrine cells. J Biol Chem 2004; 279: 8029-8037
38 Liu Q, Bee MS, Schonbrunn A. Site specificity of agonist and second messenger-activated kinases for somatostatin receptor subtype 2A (Sst2A) phosphorylation. Mol Pharmacol 2009; 76: 68-80
39 Hipkin RW, Friedman J, Clark RB, Eppler CM, Schonbrunn A. Agonist-induced desensitization, internalization, and phosphorylation of the sst2A somatostatin receptor. J Biol Chem 1997; 272: 13869-13876
40 Nagel F, Doll C, Pöll F, Kliewer A, Schröder H, Schulz S. Structural determinants of agonist-selective signaling at the sst(2A) somatostatin receptor. Mol Endocrinol 2011; 25: 859-866
41 Lehmann A, Kliewer A, Schütz D, Nagel F, Stumm R, Schulz S. Carboxyl-terminal multi-site phosphorylation regulates internalization and desensitization of the human sst2 somatostatin receptor. Mol Cell Endocrinol 2014; 387: 44-51
42 Liu Q, Reubi JC, Wang Y, Knoll BJ, Schonbrunn A. In vivo phosphorylation of the somatostatin 2A receptor in human tumors. J Clin Endocrinol Metab 2003; 88: 6073-6079
43 Pöll F, Lehmann D, Illing S, Ginj M, Jacobs S, Lupp A, Stumm R, Schulz S. Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation. Mol Endocrinol 2010; 24: 436-446
44 Hipkin RW, Wang Y, Schonbrunn A. Protein kinase C activation stimulates the phosphorylation and internalization of the sst2A somatostatin receptor. J Biol Chem 2000; 275: 5591-5599
45 Kao YJ, Ghosh M, Schonbrunn A. Ligand-dependent mechanisms of sst2A receptor trafficking: role of site-specific phosphorylation and receptor activation in the actions of biased somatostatin agonists. Mol Endocrinol 2011; 25: 1040-1054
46 Koenig JA, Kaur R, Dodgeon I, Edwardson JM, Humphrey PP. Fates of endocytosed somatostatin sst2 receptors and associated agonists. Biochem J 1998; 336: 291-298
47 Ghosh M, Schonbrunn A. Differential temporal and spatial regulation of somatostatin receptor phosphorylation and dephosphorylation. J Biol Chem 2011; 286: 13561-13573
48 Lesche S, Lehmann D, Nagel F, Schmid HA, Schulz S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J Clin Endocrinol Metab 2009; 94: 654-661
49 Peverelli E, Giardino E, Vitali E, Treppiedi D, Lania AG, Mantovani G. Filamin A in somatostatin and dopamine receptor regulation in pituitary and the role of cAMP/PKA dependent phosphorylation. Horm Metab Res 2014; 46: 845-853
50 Cambiaghi V, Vitali E, Morone D, Peverelli E, Spada A, Mantovani G, Lania AG. Identification of human Somatostatin Receptor 2 (SST2) domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line. Endocrine 2016 [Epub ahead of print]
51 Kohout TA, Lefkowitz RJ. Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol 2003; 63: 9-18
52 Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 2002; 115: 455-465
53 Gurevich VV, Gurevich EV. The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol Ther 2006; 110: 465-502
54 Vishnivetskiy SA, Schubert C, Climaco GC, Gurevich YV, Velez MG, Gurevich VV. An additional phosphate-binding element in arrestin molecule. Implications for the mechanism of arrestin activation. J Biol Chem 2000; 275: 41049-41057
55 DeFea KA, Zalevsky J, Thoma MS, Déry O, Mullins RD, Bunnett NW. Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 2000; 148: 1267-1281
56 Lefkowitz RJ, Whalen EJ. Beta-arrestins: traffic cops of cell signaling. Curr Opin Cell Biol 2004; 16: 162-168
57 Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science 2005; 308: 512-517
58 Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS. Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 2000; 275: 17201-17210
59 Oakley RH, Laporte SA, Holt JA, Barak LS, Caron MG. Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis. J Biol Chem 2001; 276: 19452-19460
60 Liu Q, Dewi DA, Liu W, Bee MS, Schonbrunn A. Distinct phosphorylation sites in the SST2A somatostatin receptor control internalization, desensitization, and arrestin binding. Mol Pharmacol 2008; 73: 292-304
61 Brasselet S, Guillen S, Vincent JP, Mazella J. Beta-arrestin is involved in the desensitization but not in the internalization of the somatostatin receptor 2A expressed in CHO cells. FEBS Lett 2002; 516: 124-128
62 Ballarè E, Persani L, Lania AG, Filopanti M, Giammona E, Corbetta S, Mantovani S, Arosio M, Beck-Peccoz P, Faglia G, Spada A. Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab 2001; 86: 3809-3814
63 Peverelli E, Lania AG, Mantovani G, Beck-Peccoz P, Spada A. Characterization of intracellular signaling mediated by human somatostatin receptor 5: role of the DRY motif and the third intracellular loop. Endocrinology 2009; 150: 3169-3176
64 Peverelli E, Busnelli M, Vitali E, Giardino E, Galés C, Lania AG, Beck-Peccoz P, Chini B, Mantovani G, Spada A. Specific roles of G(i) protein family members revealed by dissecting SST5 coupling in human pituitary cells. J Cell Sci 2013; 126: 638-644
65 Petersenn S, Heyens M, Lüdecke DK, Beil FU, Schulte HM. Absence of somatostatin receptor type 2A mutations and gip oncogene in pituitary somatotroph adenomas. Clin Endocrinol (Oxf) 2000; 52: 35-42
66 Corbetta S, Ballaré E, Mantovani G, Lania AG, Losa M, Di Blasio AM, Spada A. Somatostatin receptor subtype 2 and 5 in human GH-secreting pituitary adenomas: analysis of gene sequence and mRNA expression. Eur J Clin Invest 2001; 31: 208-214
67 Mundell SJ, Benovic JL. Selective regulation of endogenous G protein-coupled receptors by arrestins in HEK293 cells. J Biol Chem 2000; 275: 12900-12908
68 Hartwig JH, Stossel TP. Isolation and properties of actin, myosin, and a new actinbinding protein in rabbit alveolar macrophages. J Biol Chem 1975; 250: 5696-5705
69 Nakamura F, Stossel TP, Hartwig JH. The filamins: organizers of cell structure and function. Cell Adh Migr 2011; 5: 160-169
70 Stossel TP, Condeelis J, Cooley L, Hartwig JH, Noegel A, Schleicher M, Shapiro SS. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2001; 2: 138-145
71 Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R. Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A. Proc Natl Acad Sci USA 2001; 98: 5258-5263
72 Lin R, Canfield V, Levenson R. Dominant negative mutants of filamin A block cell surface expression of the D2 dopamine receptor. Pharmacology 2002; 66: 173-181
73 Cho EY, Cho DI, Park JH, Kurose H, Caron MG, Kim KM. Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. Mol Endocrinol 2007; 21: 2242-2254
74 Noam Y, Ehrengruber MU, Koh A, Feyen P, Manders EM, Abbott GW, Wadman WJ, Baram TZ. Filamin A promotes dynamin-dependent internalization of hyperpolarization-activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons. J Biol Chem 2014; 289: 5889-5903
75 Muriel O, Echarri A, Hellriegel C, Pavón DM, Beccari L, Del Pozo MA. Phosphorylated filamin A regulates actin-linked caveolae dynamics. J Cell Sci 2011; 124: 2763-2776
76 Minsaas L, Planagumà J, Madziva M, Krakstad BF, Masià-Balagué M, Katz AA, Aragay AM. Filamin a binds to CCR2B and regulates its internalization. PLoS One 2010; 5: e12212
77 Onoprishvili I, Andria ML, Kramer HK, Ancevska-Taneva N, Hiller JM, Simon EJ. Interaction between the mu opioid receptor and filamin A is involved in receptor regulation and trafficking. Mol Pharmacol 2003; 64: 1092-1100
78 Seck T, Baron R, Horne WC. Binding of filamin to the C-terminal tail of the calcitonin receptor controls recycling. J Biol Chem 2003; 278: 10408-10416
79 Zhang M, Breitwieser GE. High affinity interaction with filamin A protects against calcium-sensing receptor degradation. J Biol Chem 2005; 280: 11140-11146
80 Thelin WR, Chen Y, Gentzsch M, Kreda SM, Sallee JL, Scarlett CO, Borchers CH, Jacobson K, Stutts MJ, Milgram SL. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest 2007; 117: 364-374
81 Beekman JM, van der Poel CE, van der Linden JA, van den Berg DL, van den Berghe PV, van de Winkel JG, Leusen JH. Filamin A stabilizes Fc gamma RI surface expression and prevents its lysosomal routing. J Immunol 2008; 180: 3938-3945
82 Liu G, Thomas L, Warren RA, Enns CA, Cunningham CC, Hartwig JH, Thomas G. Cytoskeletal protein ABP-280 directs the intracellular trafficking of furin and modulates proprotein processing in the endocytic pathway. J Cell Biol 1997; 139: 1719-1733
83 Fiori JL, Zhu TN, O’Connell MP, Hoek KS, Indig FE, Frank BP, Morris C, Kole S, Hasskamp J, Elias G, Weeraratna AT, Bernier M. Filamin A modulates kinase activation and intracellular trafficking of epidermal growth factor receptors in human melanoma cells. Endocrinology 2009; 150: 2551-2560
84 Najib S, Saint-Laurent N, Estève JP, Schulz S, Boutet-Robinet E, Fourmy D, Lättig J, Mollereau C, Pyronnet S, Susini C, Bousquet C. A switch of G protein-coupled receptor binding preference from phosphoinositide 3-kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway. Mol Cell Biol 2012; 32: 1004-1016
85 Vitali E, Cambiaghi V, Zerbi A, Carnaghi C, Colombo P, Peverelli E, Spada A, Mantovani G, Lania AG. Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours. Endocr Relat Cancer 2016; 23: 181-190
86 Donangelo I, Melmed S. Treatment of acromegaly: future. Endocrine 2005; 28: 123-128
87 Colao A, Faggiano A, Pivonello R. Somatostatin analogues: treatment of pituitary and neuroendocrine tumors. Prog Brain Res 2010; 182: 281-294
88 Lewis I, Bauer W, Albert R, Chandramouli N, Pless J, Weckbecker G, Bruns C. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J Med Chem 2003; 46: 2334-2344
89 Waser B, Cescato R, Liu Q, Kao YJ, Körner M, Christ E, Schonbrunn A, Reubi JC. Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. Am J Pathol 2012; 180: 1942-1949
90 Hofland LJ, van der Hoek J, van Koetsveld PM, de Herder WW, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, Feelders R, van der Lely AJ, Beckers A, Lamberts SW. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab 2004; 89: 1577-1585
91 Petersenn S, Schopohl J, Barkan A, Mohideen P, Colao A, Abs R, Buchelt A, Ho YY, Hu K, Farrall AJ, Melmed S, Biller BM. Pasireotide Acromegaly Study Group . Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial. J Clin Endocrinol Metab 2010; 95: 2781-2789
92 Petersenn S, Farrall AJ, De Block C, Melmed S, Schopohl J, Caron P, Cuneo R, Kleinberg D, Colao A, Ruffin M, Hermosillo Reséndiz K, Hughes G, Hu K, Barkan A. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. Pituitary 2014; 17: 132-140
93 Grant M, Alturaihi H, Jaquet P, Collier B, Kumar U. Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization. Mol Endocrinol 2008; 22: 2278-2292
94 Durán-Prado M, Malagón MM, Gracia-Navarro F, Castaño JP. Dimerization of G protein-coupled receptors: new avenues for somatostatin receptor signalling, control and functioning. Mol Cell Endocrinol 2008; 286: 63-68
95 Durán-Prado M, Saveanu A, Luque RM, Gahete MD, Gracia-Navarro F, Jaquet P, Dufour H, Malagón MM, Culler MD, Barlier A, Castaño JP. A potential inhibitory role for the new truncated variant of somatostatin receptor 5, sst5TMD4, in pituitary adenomas poorly responsive to somatostatin analogs. J Clin Endocrinol Metab 2010; 95: 2497-2502
96 Luque RM, Ibáñez-Costa A, Neto LV, Taboada GF, Hormaechea-Agulla D, Kasuki L, Venegas-Moreno E, Moreno-Carazo A, Gálvez MÁ, Soto-Moreno A, Kineman RD, Culler MD, Gahete MD, Gadelha MR, Castaño JP. Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Lett 2015; 359: 299-306
97 Durán-Prado M, Gahete MD, Hergueta-Redondo M, Martínez-Fuentes AJ, Córdoba-Chacón J, Palacios J, Gracia-Navarro F, Moreno-Bueno G, Malagón MM, Luque RM, Castaño JP. The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells. Oncogene 2012; 31: 2049-2061
98 Durán-Prado M, Gahete MD, Martínez-Fuentes AJ, Luque RM, Quintero A, Webb SM, Benito-López P, Leal A, Schulz S, Gracia-Navarro F, Malagón MM, Castaño JP. Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J Clin Endocrinol Metab 2009; 94: 2634-2343
99 Kim KM, Gainetdinov RR, Laporte SA, Caron MG, Barak LS. G protein-coupled receptor kinase regulates dopamine D3 receptor signaling by modulating the stability of a receptor-filamin-beta-arrestin complex. A case of autoreceptor regulation. J Biol Chem 2005; 280: 12774-12780
100 Scott MG, Pierotti V, Storez H, Lindberg E, Thuret A, Muntaner O, Labbé-Jullié C, Pitcher JA, Marullo S. Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins. Mol Cell Biol 2006; 26: 3432-3445