Role of Phosphodiesterases on the Function of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Pituitary Gland and on the Evaluation of AIP Gene Variants

Abstract

Familial isolated pituitary adenoma (FIPA) is caused in about 20% of cases by loss-of-function germline mutations in the AIP gene. Patients harboring AIP mutations usually present with somatotropinomas resulting either in gigantism or young-onset acromegaly. AIP encodes for a co-chaperone protein endowed with tumor suppressor properties in somatotroph cells. Among other mechanisms proposed to explain this function, a regulatory effect over the 3′,5′-cyclic adenosine monophosphate (cAMP) signaling pathway seems to play a prominent role. In this setting, the well-known interaction between AIP and 2 different isoforms of phosphodiesterases (PDEs), PDE2A3 and PDE4A5, is of particular interest. While the interaction with over-expressed AIP does not seem to affect PDE2A3 function, the reported effect on PDE4A5 is, in contrast, reduced enzymatic activity. In this review, we explore the possible implications of these molecular interactions for the function of somatotroph cells. In particular, we discuss how both PDEs and AIP could act as negative regulators of the cAMP pathway in the pituitary, probably both by shared and independent mechanisms. Moreover, we describe how the evaluation of the AIP-PDE4A5 interaction has proven to be a useful tool for testing AIP mutations, complementing other in silico, in vitro, and in vivo analyses. Improved assessment of the pathogenicity of AIP mutations is indeed paramount to provide adequate guidance for genetic counseling and clinical screening in AIP mutation carriers, which can lead to prospective diagnosis of pituitary adenomas.

Key words

phosphodiesterases - AIP - FIPA - acromegaly - gigantism

Publication History

Received: 28 November 2016

Accepted: 22 February 2017

Article published online:
20 April 2017

• References

• 1 Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Ciccarelli E, Brue T, Ferolla P, Emy P, Colao A, De ME, Lecomte P, Penfornis F, Delemer B, Bertherat J, Wemeau JL, De HW, Archambeaud F, Stevenaert A, Calender A, Murat A, Cavagnini F, Beckers A. Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 2006; 91: 3316-3323
• 2 Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gundogdu S, De ME, Makinen MJ, Launonen V, Karhu A, Aaltonen LA. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006; 312: 1228-1230
• 3 Daly AF, Tichomirowa MA, Petrossians P, Heliovaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De ME, Montanana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabate MI, Villa C, Popelier M, Salvatori R, Jennings J, Longas AF, Labarta Aizpun JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De HW, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 2010; 95: E373-E383
• 4 Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 2013; 34: 239-277
• 5 Hernández-Ramírez LC, Gabrovska P, Dénes J, Stals K, Trivellin G, Tilley D, Ferraù F, Evanson J, Ellard S, Grossman AB, Roncaroli F, Gadelha MR, Consortium TIF . Korbonits M. Landscape of familial isolated and young-onset pituitary adenomas: Prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab 2015; 100: E1242-E1254
• 6 Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenicky P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371: 2363-2374
• 7 Beckers A, Lodish M, Giampaolo T, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong C, Caberg JH, Verrua E, Naves LA, Cheetham T, Young J, Lysy P, Petrossians P, Cotterill A, Shah N, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barcelos BG, Casulari LA, Neggers S, Salvatori R, Jaffrain-Rea ML, Zacharin M, Lecumberri SB, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield E, Bours V, Liu P, de Herder WW, Pellegata NS, Lupski JR, Daly AF, Stratakis CA. X-linked acrogigantism (X-LAG) syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer 2015; 22: 353-367
• 8 Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L, de Herder WW, Naves LA, Metzger D, Cuny T, Rabl W, Shah N, Jaffrain-Rea ML, Zatelli MC, Faucz FR, Castermans E, Nanni-Metellus I, Lodish M, Muhammad A, Palmeira L, Potorac I, Mantovani G, Neggers S, Klein M, Barlier A, Liu P, Ouafik L, Bours V, Lupski JR, Stratakis CA, Beckers A. Somatic mosaicism underlies X-linked acrogigantism (XLAG) syndrome in sporadic male subjects. Endocr Relat Cancer 2016; 23: 221-233
• 9 Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, Kapur S, Caimari F, Evanson J, Ferraù F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramírez-Rentería C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun 2016; 4: 56
• 10 Gordon RJ, Bell J, Chung WK, David R, Oberfield SE, Wardlaw SL. Childhood acromegaly due to X-linked acrogigantism: long term follow-up. Pituitary 2016; 19: 560-564
• 11 Beckers A, Fernandes D, Fina F, Novak M, Abati A, Rostomyan L, Thiry A, Ouafik L, Pasture B, Pinhasi R, Daly AF. Paleogenetic study of ancient DNA suggestive of X-Linked acrogigantism. Endocr Relat Cancer 2017; 24: L17-L20
• 12 Gadelha MR, Prezant TR, Une KN, Glick RP, Moskal SF, Vaisman M, Melmed S, Kineman RD, Frohman LA. Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J Clin Endocrinol Metab 1999; 84: 249-256
• 13 Gadelha MR, Une KN, Rohde K, Vaisman M, Kineman RD, Frohman LA. Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab 2000; 85: 707-714
• 14 Frohman LA. Isolated familial somatotropinomas: clinical and genetic considerations. Trans Am Clin Climatol Assoc 2003; 114: 165-177
• 15 Xekouki P, Mastroyiannis SA, Avgeropoulos D, de la Luz SM, Trivellin G, Gourgari EA, Lyssikatos C, Quezado M, Patronas N, Kanaka-Gantenbein C, Chrousos GP, Stratakis CA. Familial pituitary apoplexy as the only presentation of a novel AIP mutation. Endocr Relat Cancer 2013; 20: L11-L14
• 16 Formosa R, Xuereb-Anastasi A, Vassallo J. Aip regulates cAMP signalling and GH secretion in GH3 cells. Endocr Relat Cancer 2013; 20: 495-505
• 17 Tuominen I, Heliovaara E, Raitila A, Rautiainen MR, Mehine M, Katainen R, Donner I, Aittomaki V, Lehtonen HJ, Ahlsten M, Kivipelto L, Schalin-Jantti C, Arola J, Hautaniemi S, Karhu A. AIP inactivation leads to pituitary tumorigenesis through defective Galphai-cAMP signaling. Oncogene 2015; 34: 1174-1184
• 18 Ensembl. Gene: AIP ENSG00000110711. http://grch37.ensembl.org/Homo_sapiens/Gene/Summary?db = core;g = ENSG00000110711; r = 11:67250512-67258574 Access date: 17-10-2016
• 19 Ma Q, Whitlock Jr. JP. A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 1997; 272: 8878-8884
• 20 Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA. Characterization of the Ah receptor-associated protein, ARA9. J Biol Chem 1998; 273: 33580-33587
• 21 Morgan RM, Hernández-Ramírez LC, Trivellin G, Zhou L, Roe SM, Korbonits M, Prodromou C. Structure of the TPR domain of AIP: Lack of client protein interaction with the C-terminal alpha-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition. PLoS One 2012; 7: e53339
• 22 Linnert M, Haupt K, Lin YJ, Kissing S, Paschke AK, Fischer G, Weiwad M, Lucke C. NMR assignments of the FKBP-type PPIase domain of the human aryl-hydrocarbon receptor-interacting protein (AIP). Biomol NMR Assign 2012; 6: 209-212
• 23 The Uniprot Consortium . UniProt: a hub for protein information (http://www.uniprot.org/). Nucleic Acids Res 2015; 43: D204-D212
• 24 NCBI Gene. AIP aryl hydrocarbon receptor interacting protein [Homo sapiens (human)].http://www.ncbi.nlm.nih.gov/gene/9049#reference- sequences Access date: 5-4-2015
• 25 Dull AB, Carlson DB, Petrulis JR, Perdew GH. Characterization of the phosphorylation status of the hepatitis B virus X-associated protein 2. Arch Biochem Biophys 2002; 406: 209-221
• 26 Meyer BK, Petrulis JR, Perdew GH. Aryl hydrocarbon (Ah) receptor levels are selectively modulated by hsp90-associated immunophilin homolog XAP2. Cell Stress Chaperones 2000; 5: 243-254
• 27 Kuzhandaivelu N, Cong YS, Inouye C, Yang WM, Seto E. XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation. Nucleic Acids Res 1996; 24: 4741-4750
• 28 Carver LA, Bradfield CA. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J Biol Chem 1997; 272: 11452-11456
• 29 Linnert M, Lin YJ, Manns A, Haupt K, Paschke AK, Fischer G, Weiwad M, Lucke C. The FKBP-type domain of the human aryl hydrocarbon receptor-interacting protein reveals an unusual Hsp90 interaction. Biochemistry 2013; 52: 2097-2107
• 30 EMBL-EBI. Expression Atlas. http://www.ebi.ac.uk/gxa/query?geneQuery = AIP&exactMatch = true&_exactMatch = on&organism = Homo + sapiens&condition = Access date: 5-4-2015
• 31 Cunningham F, Amode MR, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, Gil L, Giron CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Johnson N, Juettemann T, Kahari AK, Keenan S, Martin FJ, Maurel T, McLaren W, Murphy DN, Nag R, Overduin B, Parker A, Patricio M, Perry E, Pignatelli M, Riat HS, Sheppard D, Taylor K, Thormann A, Vullo A, Wilder SP, Zadissa A, Aken BL, Birney E, Harrow J, Kinsella R, Muffato M, Ruffier M, Searle SM, Spudich G, Trevanion SJ, Yates A, Zerbino DR, Flicek P. Ensembl 2015. Nucleic Acids Res 2015; 43: D662-D669
• 32 Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S, Chahal HS, Igreja SC, Jordan S, Rowe J, Stolbrink M, Christian HC, Wray J, Bishop-Bailey D, Berney DM, Wass JA, Popovic V, Ribeiro-Oliveira Jr. A, Gadelha MR, Monson JP, Akker SA, Davis JR, Clayton RN, Yoshimoto K, Iwata T, Matsuno A, Eguchi K, Musat M, Flanagan D, Peters G, Bolger GB, Chapple JP, Frohman LA, Grossman AB, Korbonits M. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab 2008; 93: 2390-2401
• 33 Jaffrain-Rea ML, Angelini M, Gargano D, Tichomirowa MA, Daly AF, Vanbellinghen JF, D’Innocenzo E, Barlier A, Giangaspero F, Esposito V, Ventura L, Arcella A, Theodoropoulou M, Naves LA, Fajardo C, Zacharieva S, Rohmer V, Brue T, Gulino A, Cantore G, Alesse E, Beckers A. Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 2009; 16: 1029-1043
• 34 Barik S. Immunophilins: for the love of proteins. Cell Mol Life Sci 2006; 63: 2889-2900
• 35 Guy NC, Garcia YA, Sivils JC, Galigniana MD, Cox MB. Functions of the Hsp90-binding FKBP immunophilins. Subcell Biochem 2015; 78: 35-68
• 36 D’Andrea LD, Regan L. TPR proteins: the versatile helix. Trends Biochem Sci 2003; 28: 655-662
• 37 Zeytuni N, Zarivach R. Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module. Structure 2012; 20: 397-405
• 38 Perdew GH. Association of the Ah receptor with the 90-kDa heat shock protein. J Biol Chem 1988; 263: 13802-13805
• 39 Chen HS, Perdew GH. Subunit composition of the heteromeric cytosolic aryl hydrocarbon receptor complex. J Biol Chem 1994; 269: 27554-27558
• 40 Nair SC, Toran EJ, Rimerman RA, Hjermstad S, Smithgall TE, Smith DF. A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor. Cell Stress Chaperones 1996; 1: 237-250
• 41 Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Mol Cell Biol 1998; 18: 978-988
• 42 Kazlauskas A, Sundstrom S, Poellinger L, Pongratz I. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol Cell Biol 2001; 21: 2594-2607
• 43 Ramadoss P, Petrulis JR, Hollingshead BD, Kusnadi A, Perdew GH. Divergent roles of hepatitis B virus X-associated protein 2 (XAP2) in human versus mouse Ah receptor complexes. Biochemistry 2004; 43: 700-709
• 44 Whitlock Jr. JP. Mechanistic aspects of dioxin action. Chem Res Toxicol 1993; 6: 754-763
• 45 Bell DR, Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90. J Biol Chem 2000; 275: 36407-36414
• 46 Beischlag TV, Luis MJ, Hollingshead BD, Perdew GH. The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 2008; 18: 207-250
• 47 Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci 2011; 124: 1-22
• 48 Nguyen LP, Bradfield CA. The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 2008; 21: 102-116
• 49 Nukaya M, Lin BC, Glover E, Moran SM, Kennedy GD, Bradfield CA. The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin-induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes. J Biol Chem 2010; 285: 35599-35605
• 50 Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von DA, Wick W, Platten M. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011; 478: 197-203
• 51 Yano M, Terada K, Mori M. AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins. J Cell Biol 2003; 163: 45-56
• 52 Kang BH, Altieri DC. Regulation of survivin stability by the aryl hydrocarbon receptor-interacting protein. J Biol Chem 2006; 281: 24721-24727
• 53 Kang BH, Xia F, Pop R, Dohi T, Socolovsky M, Altieri DC. Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein. J Biol Chem 2011; 286: 16758-16767
• 54 Liu T, Daniels CK, Cao S. Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacol Ther 2012; 136: 354-374
• 55 Truman AW, Kristjansdottir K, Wolfgeher D, Hasin N, Polier S, Zhang H, Perrett S, Prodromou C, Jones GW, Kron SJ. CDK-dependent Hsp70 phosphorylation controls G1 cyclin abundance and cell-cycle progression. Cell 2012; 151: 1308-1318
• 56 Kashuba E, Kashuba V, Pokrovskaja K, Klein G, Szekely L. Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen. Oncogene 2000; 19: 1801-1806
• 57 Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res 2006; 34: D535-D539
• 58 Trivellin G, Korbonits M. AIP and its interacting partners. J Endocrinol 2011; 210: 137-155
• 59 Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725-748
• 60 Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 2006; 109: 366-398
• 61 Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007; 76: 481-511
• 62 HUGO Gene Nomenclature Committee. Gene Family: Phosphodiesterases (PDE). http://www.genenames.org/cgi-bin/genefamilies/set/681 Access date: 06-10-2016
• 63 Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91: 651-690
• 64 Ke H, Wang H. Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr Top Med Chem 2007; 7: 391-403
• 65 Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science 2000; 288: 1822-1825
• 66 Azevedo MF, Faucz FR, Bimpaki E, Horvath A, Levy I, de Alexandre RB, Ahmad F, Manganiello V, Stratakis CA. Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev 2014; 35: 195-233
• 67 Bolger G, Michaeli T, Martins St T, John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K. A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 1993; 13: 6558-6571
• 68 Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des 2010; 16: 1114-1125
• 69 Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C, Houslay MD. Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J 1997; 328 Pt 2 539-548
• 70 Bolger GB, Phosphodiesterase isoforms- an annotated list In: Beavo JA, Francis SH, Houslay MD. (eds.). Cyclic nucleotide phosphodiesterases in health and disease. Boca Raton, FL, USA: CRC Press; 2007
• 71 Eskandari N, Mirmosayyeb O, Bordbari G, Bastan R, Yousefi Z, Andalib A. A short review on structure and role of cyclic-3',5'-adenosine monophosphate-specific phosphodiesterase 4 as a treatment tool. J Res Pharm Pract 2015; 4: 175-181
• 72 Engels P, Fichtel K, Lubbert H. Expression and regulation of human and rat phosphodiesterase type IV isogenes. FEBS Lett 1994; 350: 291-295
• 73 Bolger GB, Bizzi MF, Pinheiro SV, Trivellin G, Smoot L, Accavitti MA, Korbonits M, Ribeiro-Oliveira Jr. A. cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Endocr Relat Cancer 2016; 23: 419-431
• 74 Huston E, Beard M, McCallum F, Pyne NJ, Vandenabeele P, Scotland G, Houslay MD. The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. J Biol Chem 2000; 275: 28063-28074
• 75 Beard MB, Huston E, Campbell L, Gall I, McPhee I, Yarwood S, Scotland G, Houslay MD. In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting. Cell Signal 2002; 14: 453-465
• 76 Bolger GB, Peden AH, Steele MR, MacKenzie C, McEwan DG, Wallace DA, Huston E, Baillie GS, Houslay MD. Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J Biol Chem 2003; 278: 33351-33363
• 77 Bajpai M, Fiedler SE, Huang Z, Vijayaraghavan S, Olson GE, Livera G, Conti M, Carr DW. AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa. Biol Reprod 2006; 74: 109-118
• 78 Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, Beavo JA. The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci USA 2002; 99: 13260-13265
• 79 Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58: 488-520
• 80 Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K. Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase. Gene 1997; 191: 89-95
• 81 Sadhu K, Hensley K, Florio VA, Wolda SL. Differential expression of the cyclic GMP-stimulated phosphodiesterase PDE2A in human venous and capillary endothelial cells. J Histochem Cytochem 1999; 47: 895-906
• 82 Stephenson DT, Coskran TM, Wilhelms MB, Adamowicz WO, O'Donnell MM, Muravnick KB, Menniti FS, Kleiman RJ, Morton D. Immunohistochemical localization of phosphodiesterase 2A in multiple mammalian species. J Histochem Cytochem 2009; 57: 933-949
• 83 Lennox C, Trivellin G, Korbonits M. Evaluation of the interaction of phosphodiesterases 2A and 4A5 with the aryl hydrocarbon receptor interacting protein in pituitary cells. Soc Endocrinol BES 2011; Endocr Abstr 2011: P245 www.endocrine-abstracts.org
• 84 de Oliveira SK, Hoffmeister M, Gambaryan S, Muller-Esterl W, Guimaraes JA, Smolenski AP. Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor. J Biol Chem 2007; 282: 13656-13663
• 85 de Oliveira SK, Smolenski A. Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling. Biochem Pharmacol 2009; 77: 723-733
• 86 Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE. Insights into G protein structure, function, and regulation. Endocr Rev 2003; 24: 765-781
• 87 Kirschner LS. PRKAR1A and the evolution of pituitary tumors. Mol Cell Endocrinol 2010; 326: 3-7
• 88 Gadelha MR, Kasuki L, Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab 2013; 24: 238-246
• 89 Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S, Lupp A, Schulz S, Ansorge O, Karavitaki N, Carlsen E, Wass JA, Grossman AB, Korbonits M. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J Clin Endocrinol Metab 2012; 97: E1411-E1420
• 90 Kasuki L, Vieira NL, Wildemberg LE, Colli LM, De CM, Takiya CM, Gadelha MR. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression. Endocr Relat Cancer 2012; 19: L25-L29
• 91 Kasuki Jomori de PL, Vieira NL, Armondi Wildemberg LE, Gasparetto EL, Marcondes J, de Almeida NB, Takiya CM, Gadelha MR. Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. Neuroendocrinology 2011; 94: 39-48
• 92 Jaffrain-Rea ML, Rotondi S, Turchi A, Occhi G, Barlier A, Peverelli E, Rostomyan L, Defilles C, Angelini M, Oliva MA, Ceccato F, Maiorani O, Daly AF, Esposito V, Buttarelli F, Figarella-Branger D, Giangaspero F, Spada A, Scaroni C, Alesse E, Beckers A. Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr Relat Cancer 2013; 20: 753-766
• 93 Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, Pagotto U, Stalla GK. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res 2006; 66: 1576-1582
• 94 Cervia D, Bagnoli P. An update on somatostatin receptor signaling in native systems and new insights on their pathophysiology. Pharmacol Ther 2007; 116: 322-341
• 95 Velardez MO, De Laurentiis A, del Carmen Diaz M, Lasaga M, Pisera D, Seilicovich A, Duvilanski BH. Role of phosphodiesterase and protein kinase G on nitric oxide-induced inhibition of prolactin release from the rat anterior pituitary. Eur J Endocrinol 2000; 143: 279-284
• 96 Lania A, Persani L, Ballare E, Mantovani S, Losa M, Spada A. Constitutively active Gs alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas. J Clin Endocrinol Metab 1998; 83: 1624-1628
• 97 Persani L, Borgato S, Lania A, Filopanti M, Mantovani G, Conti M, Spada A. Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs(alpha) mutations. J Clin Endocrinol Metab 2001; 86: 3795-3800
• 98 Peverelli E, Ermetici F, Filopanti M, Elli FM, Ronchi CL, Mantovani G, Ferrero S, Bosari S, Beck-Peccoz P, Lania A, Spada A. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. Eur J Endocrinol 2009; 161: 687-694
• 99 Peverelli E, Mantovani G, Lania AG, Spada A. cAMP in the pituitary: an old messenger for multiple signals. J Mol Endocrinol 2014; 52: R67-R77
• 100 MacKenzie KF, Wallace DA, Hill EV, Anthony DF, Henderson DJ, Houslay DM, Arthur JS, Baillie GS, Houslay MD. Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. Biochem J 2011; 435: 755-769
• 101 Ramamurthy V, Niemi GA, Reh TA, Hurley JB. Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase. Proc Natl Acad Sci USA 2004; 101: 13897-13902
• 102 Williams F, Hunter S, Bradley L, Chahal HS, Storr HL, Akker SA, Kumar AV, Orme SM, Evanson J, Abid N, Morrison PJ, Korbonits M, Atkinson AB. Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. J Clin Endocrinol Metab 2014; 99: 1122-1131
• 103 Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S, Grossman AB, Korbonits M. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat. 2010: 31: 950–960
• 104 Hernández-Ramírez LC, Martucci F, Morgan RM, Trivellin G, Tilley D, Ramos-Guajardo N, Iacovazzo D, D'Acquisto F, Prodromou C, Korbonits M. Rapid proteasomal degradation of mutant proteins is the primary mechanism leading to tumorigenesis in patients with missense AIP mutations. J Clin Endocrinol Metab 2016; 101: 3144-3154
• 105 Aflorei ED, Radian S, Chen C, Klapholz B, Brown N, Stanewsky R, Korbonits M. Functional homology between human and fruitfly AIP protein - an in vivo assay system to test the pathogenicity of AIP mutations. Endocr Rev 2015; 36: (2_Meeting Abstracts): SAT-440
• 106 Rosenberg D, Groussin L, Jullian E, Perlemoine K, Bertagna X, Bertherat J. Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann NY Acad Sci 2002; 968: 65-74
• 107 Tomic M, Kucka M, Kretschmannova K, Li S, Nesterova M, Stratakis CA, Stojilkovic SS. Role of nonselective cation channels in spontaneous and protein kinase A-stimulated calcium signaling in pituitary cells. Am J Physiol Endocrinol Metab 2011; 301: E370-E379
• 108 Kleuss C, Raw AS, Lee E, Sprang SR, Gilman AG. Mechanism of GTP hydrolysis by G-protein alpha subunits. Proc Natl Acad Sci USA 1994; 91: 9828-9831
• 109 Griffioen G, Thevelein JM. Molecular mechanisms controlling the localisation of protein kinase A. Curr Genet 2002; 41: 199-207
• 110 Ben-Shlomo A, Melmed S. Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 2010; 21: 123-133