Cyclic Nucleotide Phosphodiesterase 3 Signaling Complexes

 

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Abstract

The superfamily of cyclic nucleotide phosphodiesterases is comprised of 11 gene families. By hydrolyzing cAMP and cGMP, PDEs are major determinants in the regulation of intracellular concentrations of cyclic nucleotides and cyclic nucleotide-dependent signaling pathways. Two PDE3 subfamilies, PDE3A and PDE3B, have been described. PDE3A and PDE3B hydrolyze cAMP and cGMP with high affinity in a mutually competitive manner and are regulators of a number of important cAMP- and cGMP-mediated processes. PDE3B is relatively more highly expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, and pancreatic β-cells, whereas PDE3A is more highly expressed in heart, platelets, vascular smooth muscle cells, and oocytes. Major advances have been made in understanding the different physiological impacts and biochemical basis for recruitment and subcellular localizations of different PDEs and PDE-containing macromolecular signaling complexes or signalosomes. In these discrete compartments, PDEs control cyclic nucleotide levels and regulate specific physiological processes as components of individual signalosomes which are tethered at specific locations and which contain PDEs together with cyclic nucleotide-dependent protein kinases (PKA and PKG), adenylyl cyclases, Epacs (guanine nucleotide exchange proteins activated by cAMP), phosphoprotein phosphatases, A-Kinase anchoring proteins (AKAPs), and pathway-specific regulators and effectors. This article highlights the identification of different PDE3A- and PDE3B-containing signalosomes in specialized subcellular compartments, which can increase the specificity and efficiency of intracellular signaling and be involved in the regulation of different cAMP-mediated metabolic processes.

• References

• 1 Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007; 76: 481-511
  Google Scholar
• 2 Miki T, Taira M, Hockman S, Shimada F, Lieman J, Napolitano M, Ward D, Taira M, Makino H, Manganiello VC. Characterization of the cDNA and gene encoding human PDE3B, the cGIP1 isoform of the human cyclic GMP-inhibited cyclic nucleotide phosphodiesterase family. Genomics 1996; 36: 476-485
  CrossrefPubMedGoogle Scholar
• 3 Lobbert RW, Winterpacht A, Seipel B, Zabel BU. Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A) – a gene involved in fat metabolism located at 11p 15.1. Genomics 1996; 37: 211-218
  CrossrefPubMedGoogle Scholar
• 4 Kasuya J, Goko H, Fujita-Yamaguchi Y. Multiple transcripts for the human cardiac form of the cGMP-inhibited cAMP phosphodiesterase. J Biol Chem 1995; 270: 14305-14312
  CrossrefPubMedGoogle Scholar
• 5 Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC, Movsesian MA. Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem 2005; 280: 39168-39174
  CrossrefPubMedGoogle Scholar
• 6 Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59: 367-374
  CrossrefPubMedGoogle Scholar
• 7 Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res 2007; 100: 309-327
  CrossrefPubMedGoogle Scholar
• 8 Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006; 58: 488-520
  CrossrefPubMedGoogle Scholar
• 9 Thompson PE, Manganiello V, Degerman E. Re-discovering PDE3 inhibitors – new opportunities for a long neglected target. Curr Top Med Chem 2007; 7: 421-436
  CrossrefPubMedGoogle Scholar
• 10 Manganiello VC, Ahmad F, Choi Y, Tang Y, Trzebiatowska E, Walz H, Berger K, Shen W, Liu H, Hockman S, Park S, Holst LS, Degerman E. Regulation of cyclic nucleotide phosphodiesterase 3 (PDE3). In: Tagawa T, Murata T, Shimizu K. (eds.). Phosphodiesterase and Intracellular Signaling. Mie University Press; 2007: 101-125
  Google Scholar
• 11 Degerman E, Belfrage P, Manganiello VC. Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 1997; 272: 6823-6826
  CrossrefPubMedGoogle Scholar
• 12 Leroy MJ, Degerman E, Taira M, Murata T, Wang LH, Movsesian MA, Meacci E, Manganiello VC. Characterization of two recombinant PDE3 (cGMP-inhibited cyclic nucleotide phosphodiesterase) isoforms, RcGIP1 and HcGIP2, expressed in NIH 3006 murine fibroblasts and Sf9 insect cells. Biochemistry 1996; 35: 10194-10202
  CrossrefPubMedGoogle Scholar
• 13 Nilsson R, Ahmad F, Sward K, Andersson U, Weston M, Manganiello V, Degerman E. Plasma membrane cyclic nucleotide phosphodiesterase 3B (PDE3B) is associated with caveolae in primary adipocytes. Cell Signal 2006; 18: 1713-1721
  CrossrefPubMedGoogle Scholar
• 14 Ahmad F, Lindh R, Tang Y, Weston M, Degerman E, Manganiello VC. Insulin-induced formation of macromolecular complexes involved in activation of cyclic nucleotide phosphodiesterase 3B (PDE3B) and its interaction with PKB. Biochem J 2007; 404: 257-268
  CrossrefPubMedGoogle Scholar
• 15 Kenan Y, Murata T, Shakur Y, Degerman E, Manganiello VC. Functions of the N-terminal region of cyclic nucleotide phosphodiesterase 3 (PDE 3) isoforms. J Biol Chem 2000; 275: 12331-12338
  CrossrefPubMedGoogle Scholar
• 16 Shakur Y, Takeda K, Kenan Y, Yu ZX, Rena G, Brandt D, Houslay MD, Degerman E, Ferrans VJ, Manganiello VC. Membrane localization of cyclic nucleotide phosphodiesterase 3 (PDE3). Two N-terminal domains are required for the efficient targeting to, and association of, PDE3 with endoplasmic reticulum. J Biol Chem 2000; 275: 38749-38761
  CrossrefPubMedGoogle Scholar
• 17 Kono T, Robinson FW, Sarver JA. Insulin-sensitive phosphodiesterase. Its localization, hormonal stimulation, and oxidative stabilization. J Biol Chem 1975; 250: 7826-7835
  PubMedGoogle Scholar
• 18 Varnerin JP, Chung CC, Patel SB, Scapin G, Parmee ER, Morin NR, MacNeil DJ, Cully DF, Van der Ploeg LH, Tota MR. Expression, refolding, and purification of recombinant human phosphodiesterase 3B: definition of the N-terminus of the catalytic core. Protein Expr Purif 2004; 35: 225-236
  CrossrefPubMedGoogle Scholar
• 19 Scapin G, Patel SB, Chung C, Varnerin JP, Edmondson SD, Mastracchio A, Parmee ER, Singh SB, Becker JW, Van der Ploeg LH, Tota MR. Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity. Biochemistry 2004; 43: 6091-6100
  CrossrefPubMedGoogle Scholar
• 20 Taira M, Hockman SC, Calvo JC, Taira M, Belfrage P, Manganiello VC. Molecular cloning of the rat adipocyte hormone-sensitive cyclic GMP-inhibited cyclic nucleotide phosphodiesterase. J Biol Chem 1993; 268: 18573-18579
  PubMedGoogle Scholar
• 21 Francis SH, Colbran JL, McAllister-Lucas LM, Corbin JD. Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J Biol Chem 1994; 269: 22477-22480
  PubMedGoogle Scholar
• 22 Zhang W, Ke H, Colman RW. Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis. Mol Pharmacol 2002; 62: 514-520
  CrossrefPubMedGoogle Scholar
• 23 Zhang W, Ke H, Tretiakova AP, Jameson B, Colman RW. Identification of overlapping but distinct cAMP and cGMP interaction sites with cyclic nucleotide phosphodiesterase 3A by site-directed mutagenesis and molecular modeling based on crystalline PDE4B. Protein Sci 2001; 10: 1481-1489
  CrossrefPubMedGoogle Scholar
• 24 Ke H. Implications of PDE4 structure on inhibitor selectivity across PDE families. Int J Impot Res 2004; 16 (Suppl. 01) S24-S27
  CrossrefPubMedGoogle Scholar
• 25 Choi YH, Ekholm D, Krall J, Ahmad F, Degerman E, Manganiello VC, Movsesian MA. Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. Biochem J 2001; 353: 41-50
  CrossrefPubMedGoogle Scholar
• 26 Zmuda-Trzebiatowska E, Oknianska A, Manganiello V, Degerman E. Role of PDE3B in insulin-induced glucose uptake, GLUT-4 translocation and lipogenesis in primary rat adipocytes. Cell Signal 2006; 18: 382-390
  CrossrefPubMedGoogle Scholar
• 27 Elks ML, Manganiello VC. Antilipolytic action of insulin: role of cAMP phosphodiesterase activation. Endocrinology 1985; 116: 2119-2121
  CrossrefPubMedGoogle Scholar
• 28 Zaccolo M. cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol 2009; 158: 50-60
  CrossrefPubMedGoogle Scholar
• 29 Leroy J, Abi-Gerges A, Nikolaev VO, Richter W, Lechene P, Mazet JL, Conti M, Fischmeister R, Vandecasteele G. Spatiotemporal dynamics of beta-adrenergic cAMP signals and L-type Ca2+ channel regulation in adult rat ventricular myocytes: role of phosphodiesterases. Circ Res 2008; 102: 1091-1100
  CrossrefPubMedGoogle Scholar
• 30 Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 2010; 35: 91-100
  CrossrefPubMedGoogle Scholar
• 31 Raymond DR, Wilson LS, Carter RL, Maurice DH. Numerous distinct PKA-, or EPAC-based, signalling complexes allow selective phosphodiesterase 3 and phosphodiesterase 4 coordination of cell adhesion. Cell Signal 2007; 19: 2507-2518
  CrossrefPubMedGoogle Scholar
• 32 Scott JD, Santana LF. A-kinase anchoring proteins: getting to the heart of the matter. Circulation 2010; 121: 1264-1271
  CrossrefPubMedGoogle Scholar
• 33 Stangherlin A, Stangherlin A, Zaccolo M. Local Termination of cAMP signals: the Role of AKAP-Anchored Phosphodiesterases. J Cardiovasc Pharmacol 2011; 58: 345-353
  CrossrefPubMedGoogle Scholar
• 34 Kritzer MD, Li J, Dodge-Kafka K, Kapiloff MS. AKAPs: The architectural underpinnings of local cAMP signaling. J Mol Cell Cardiol 2011; 52: 351-358
  PubMedGoogle Scholar
• 35 Nikolaev VO, Bunemann M, Schmitteckert E, Lohse MJ, Engelhardt S. Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta1-adrenergic but locally confined beta2-adrenergic receptor-mediated signaling. Circ Res 2006; 99: 1084-1091
  Google Scholar
• 36 Leroy J, Richter W, Mika D, Castro LR, Abi-Gerges A, Xie M, Scheitrum C, Lefebvre F, Schittl J, Mateo P, Westenbroek R, Catterall WA, Charpentier F, Conti M, Fischmeister R, Vandecasteele G. Phosphodiesterase 4B in the cardiac L-type Ca(2) channel complex regulates Ca(2) current and protects against ventricular arrhythmias in mice. J Clin Invest 2011; 121: 2651-2661
  CrossrefPubMedGoogle Scholar
• 37 Houslay MD, Baillie GS, Maurice DH. cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 2007; 100: 950-966
  CrossrefPubMedGoogle Scholar
• 38 Barki-Harrington L, Perrino C, Rockman HA. Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res 2004; 63: 391-402
  CrossrefPubMedGoogle Scholar
• 39 Sin YY, Edwards HV, Li X, Day JP, Christian F, Dunlop AJ, Adams DR, Zaccolo M, Houslay MD, Baillie GS. Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)-HSP20 complex attenuates the beta-agonist induced hypertrophic response in cardiac myocytes. J Mol Cell Cardiol 2011; 50: 872-883
  CrossrefPubMedGoogle Scholar
• 40 Fan GC, Yuan Q, Song G, Wang Y, Chen G, Qian J, Zhou X, Lee YJ, Ashraf M, Kranias EG. Small heat-shock protein Hsp20 attenuates beta-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1. Circ Res 2006; 99: 1233-1242
  CrossrefPubMedGoogle Scholar
• 41 Bauman AL, Michel JJ, Henson E, Dodge-Kafka KL, Kapiloff MS. The mAKAP signalosome and cardiac myocyte hypertrophy. IUBMB Life 2007; 59: 163-169
  CrossrefPubMedGoogle Scholar
• 42 Dodge KL, Khouangsathiene S, Kapiloff MS, Mouton R, Hill EV, Houslay MD, Langeberg LK, Scott JD. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. Embo J 2001; 20: 1921-1930
  CrossrefPubMedGoogle Scholar
• 43 Dodge-Kafka KL, Bauman A, Mayer N, Henson E, Heredia L, Ahn J, McAvoy T, Nairn AC, Kapiloff MS. cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3. J Biol Chem 2010; 285: 11078-11086
  CrossrefPubMedGoogle Scholar
• 44 Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 2005; 437 (7058) 574-578
  CrossrefPubMedGoogle Scholar
• 45 Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 2005; 123: 25-35
  CrossrefPubMedGoogle Scholar
• 46 Lehnart SE, Marks AR. Phosphodiesterase 4D and heart failure: a cautionary tale. Expert Opin Ther Targets 2006; 10: 677-688
  CrossrefPubMedGoogle Scholar
• 47 Begum N, Hockman S, Manganiello VC. Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCS) via inhibition of mitogen activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins. J Biol Chem 2011; 286: 26238-26249
  CrossrefPubMedGoogle Scholar
• 48 Vinogradova TM, Sirenko S, Lyashkov AE, Younes A, Li Y, Zhu W, Yang D, Ruknudin AM, Spurgeon H, Lakatta EG. Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases. Circ Res 2008; 102: 761-769
  CrossrefPubMedGoogle Scholar
• 49 Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 2009; 122: 216-238
  CrossrefPubMedGoogle Scholar
• 50 Sun B, Li H, Shakur Y, Hensley J, Hockman S, Kambayashi J, Manganiello VC, Liu Y. Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice. Cell Signal 2007; 19: 1765-1771
  CrossrefPubMedGoogle Scholar
• 51 Lygren B, Carlson CR, Santamaria K, Lissandron V, McSorley T, Litzenberg J, Lorenz D, Wiesner B, Rosenthal W, Zaccolo M, Tasken K, Klussmann E. AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum. EMBO Rep 2007; 8: 1061-1067
  CrossrefPubMedGoogle Scholar
• 52 Kerfant BG, Gidrewicz D, Sun H, Oudit GY, Penninger JM, Backx PH. Cardiac sarcoplasmic reticulum calcium release and load are enhanced by subcellular cAMP elevations in PI3Kgamma-deficient mice. Circ Res 2005; 96: 1079-1086
  CrossrefPubMedGoogle Scholar
• 53 Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 2004; 118: 375-387
  CrossrefPubMedGoogle Scholar
• 54 Voigt P, Dorner MB, Schaefer M. Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. J Biol Chem 2006; 281: 9977-9986
  CrossrefPubMedGoogle Scholar
• 55 Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie GS, Damilano F, Dunlop AJ, Pawson C, Walser R, Levi R, Altruda F, Silengo L, Langeberg LK, Neubauer G, Heymans S, Lembo G, Wymann MP, Wetzker R, Houslay MD, Iaccarino G, Scott JD, Hirsch E. Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110gamma. Mol Cell 2011; 42: 84-95
  CrossrefPubMedGoogle Scholar
• 56 Wilson LS, Baillie GS, Pritchard LM, Umana B, Terrin A, Zaccolo M, Houslay MD, Maurice DH. A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells. J Biol Chem 2011; 286: 16285-16296
  CrossrefPubMedGoogle Scholar
• 57 Kerfant BG, Zhao D, Lorenzen-Schmidt I, Wilson LS, Cai S, Chen SR, Maurice DH, Backx PH. PI3Kgamma is required for PDE4, not PDE3, activity in subcellular microdomains containing the sarcoplasmic reticular calcium ATPase in cardiomyocytes. Circ Res 2007; 101: 400-408
  CrossrefPubMedGoogle Scholar
• 58 Penmatsa H, Zhang W, Yarlagadda S, Li C, Conoley VG, Yue J, Bahouth SW, Buddington RK, Zhang G, Nelson DJ, Sonecha MD, Manganiello V, Wine JJ, Naren AP. Compartmentalized cyclic adenosine 3′,5′-monophosphate at the plasma membrane clusters PDE3A and cystic fibrosis transmembrane conductance regulator into microdomains. Mol Biol Cell 2010; 21: 1097-1110
  CrossrefPubMedGoogle Scholar
• 59 Puxeddu E, Uhart M, Li CC, Ahmad F, Pacheco-Rodriguez G, Manganiello VC, Moss J, Vaughan M. Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity. Proc Natl Acad Sci USA 2009; 106: 6158-6163
  CrossrefPubMedGoogle Scholar
• 60 Shen W, Ahmad F, Hockman S, Ma J, Omi H, Raghavachari N, Manganiello V. Female infertility in PDE3A(-/-) mice: polo-like kinase 1 (Plk1) may be a target of protein kinase A (PKA) and involved in meiotic arrest of oocytes from PDE3A(-/-) mice. Cell Cycle 2010; 9: 4720-4734
  CrossrefPubMedGoogle Scholar
• 61 Elbatarny HS, Maurice DH. Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. Am J Physiol Endocrinol Metab 2005; 289: E695-E702
  CrossrefPubMedGoogle Scholar
• 62 Rondinone CM, Carvalho E, Rahn T, Manganiello VC, Degerman E, Smith UP. Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor. J Biol Chem 2000; 275: 10093-10098
  CrossrefPubMedGoogle Scholar
• 63 Onuma H, Osawa H, Yamada K, Ogura T, Tanabe F, Granner DK, Makino H. Identification of the insulin-regulated interaction of phosphodiesterase 3B with 14-3-3 beta protein. Diabetes 2002; 51: 3362-3367
  CrossrefPubMedGoogle Scholar
• 64 Pozuelo RM, Campbell DG, Morrice NA, Mackintosh C. Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428. Biochem J 2005; 392 (Pt 1) 163-172
  CrossrefPubMedGoogle Scholar
• 65 Hunter RW, Mackintosh C, Hers I. Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. J Biol Chem 2009; 284: 12339-12348
  CrossrefPubMedGoogle Scholar
• 66 Palmer D, Jimmo SL, Raymond DR, Wilson LS, Carter RL, Maurice DH. Protein kinase A phosphorylation of human phosphodiesterase 3B promotes 14-3-3 protein binding and inhibits phosphatase-catalyzed inactivation. J Biol Chem 2007; 282: 9411-9419
  CrossrefPubMedGoogle Scholar
• 67 Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol Cell Biol 1999; 19: 6286-6296
  CrossrefPubMedGoogle Scholar
• 68 Onuma H, Osawa H, Ogura T, Tanabe F, Nishida W, Makino H. A newly identified 50 kDa protein, which is associated with phosphodiesterase 3B, is phosphorylated by insulin in rat adipocytes. Biochem Biophys Res Commun 2005; 337: 976-982
  CrossrefPubMedGoogle Scholar
• 69 Degerman E, Rahn L, Stenson HL, Goransson O, Harndahl L, Ahmad F, Choi Y-H, Masciarelli S, Liu H, Manganiello V. Role for PDE3B in regulation of lipolysis and insulin secretion. In: LeRoith D, Taylor SI, Olefsky JM. (eds.). Diabetes Mellitus: A Fundamental and Clinical Text. 3^rd edn Philadelphia: Lippincott Raven; 2004: 373-383
  Google Scholar
• 70 Wijkander J, Landstrom TR, Manganiello V, Belfrage P, Degerman E. Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase. Endocrinology 1998; 139: 219-227
  CrossrefPubMedGoogle Scholar
• 71 Ahmad F, Gao G, Wang LM, Landstrom TR, Degerman E, Pierce JH, Manganiello VC. IL-3 and IL-4 activate cyclic nucleotide phosphodiesterases 3 (PDE3) and 4 (PDE4) by different mechanisms in FDCP2 myeloid cells. J Immunol 1999; 162: 4864-4875
  PubMedGoogle Scholar
• 72 Ahmad F, Cong LN, Stenson HL, Wang LM, Rahn LT, Pierce JH, Quon MJ, Degerman E, Manganiello VC. Cyclic nucleotide phosphodiesterase 3B is a downstream target of protein kinase B and may be involved in regulation of effects of protein kinase B on thymidine incorporation in FDCP2 cells. J Immunol 2000; 164: 4678-4688
  CrossrefPubMedGoogle Scholar
• 73 Ahmad F, Lindh R, Tang Y, Ruishalme I, Ost A, Sahachartsiri B, Stralfors P, Degerman E, Manganiello VC. Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta3-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes. Biochem J 2009; 424: 399-410
  CrossrefPubMedGoogle Scholar
• 74 Zhao AZ, Zhao H, Teague J, Fujimoto W, Beavo JA. Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. Proc Natl Acad Sci USA 1997; 94: 3223-3228
  CrossrefPubMedGoogle Scholar
• 75 Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 1998; 102: 869-873
  CrossrefPubMedGoogle Scholar
• 76 Zhao AZ, Shinohara MM, Huang D, Shimizu M, Eldar-Finkelman H, Krebs EG, Beavo JA, Bornfeldt KE. Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem 2000; 275: 11348-11354
  CrossrefPubMedGoogle Scholar
• 77 Sadler SE. Type III phosphodiesterase plays a necessary role in the growth-promoting actions of insulin, insulin-like growth factor-I, and Ha p21ras in Xenopus laevis oocytes. Mol Endocrinol 1991; 5: 1939-1946
  CrossrefPubMedGoogle Scholar
• 78 Andersen CB, Sakaue H, Nedachi T, Kovacina KS, Clayberger C, Conti M, Roth RA. Protein kinase B/Akt is essential for the insulin- but not progesterone-stimulated resumption of meiosis in Xenopus oocytes. Biochem J 2003; 369 (Pt 2) 227-238
  CrossrefPubMedGoogle Scholar
• 79 Rahn T, Ridderstrale M, Tornqvist H, Manganiello V, Fredrikson G, Belfrage P, Degerman E. Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin. FEBS Lett 1994; 350: 314-318
  CrossrefPubMedGoogle Scholar
• 80 Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 1994; 269: 3568-3573
  PubMedGoogle Scholar
• 81 Lindh R, Ahmad F, Resjo S, James P, Yang JS, Fales HM, Manganiello V, Degerman E. Multisite phosphorylation of adipocyte and hepatocyte phosphodiesterase 3B. Biochim Biophys Acta 2007; 1773: 584-592
  CrossrefPubMedGoogle Scholar
• 82 Mercier I, Jasmin JF, Pavlides S, Minetti C, Flomenberg N, Pestell RG, Frank PG, Sotgia F, Lisanti MP. Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders. Lab Invest 2009; 89: 614-623
  CrossrefPubMedGoogle Scholar
• 83 Parton RG. Caveolae and caveolins. Curr Opin Cell Biol 1996; 8: 542-548
  CrossrefPubMedGoogle Scholar
• 84 Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG. Caveolin, a protein component of caveolae membrane coats. Cell 1992; 68: 673-682
  CrossrefPubMedGoogle Scholar
• 85 Garver WS, Heidenreich RA, Erickson RP, Thomas MA, Wilson JM. Localization of the murine Niemann-Pick C1 protein to two distinct intracellular compartments. J Lipid Res 2000; 41: 673-687
  PubMedGoogle Scholar
• 86 Predescu SA, Predescu DN, Palade GE. Endothelial transcytotic machinery involves supramolecular protein-lipid complexes. Mol Biol Cell 2001; 12: 1019-1033
  CrossrefPubMedGoogle Scholar
• 87 Pelkmans L, Burli T, Zerial M, Helenius A. Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell 2004; 118: 767-780
  CrossrefPubMedGoogle Scholar
• 88 Head BP, Insel PA. Do caveolins regulate cells by actions outside of caveolae?. Trends Cell Biol 2007; 17: 51-57
  CrossrefPubMedGoogle Scholar
• 89 Harris J, Werling D, Koss M, Monaghan P, Taylor G, Howard CJ. Expression of caveolin by bovine lymphocytes and antigen-presenting cells. Immunology 2002; 105: 190-195
  CrossrefPubMedGoogle Scholar
• 90 Swaney JS, Patel HH, Yokoyama U, Head BP, Roth DM, Insel PA. Focal adhesions in (myo)fibroblasts scaffold adenylyl cyclase with phosphorylated caveolin. J Biol Chem 2006; 281: 17173-17179
  CrossrefPubMedGoogle Scholar
• 91 del Pozo MA, Balasubramanian N, Alderson NB, Kiosses WB, Grande-Garcia A, Anderson RG, Schwartz MA. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat Cell Biol 2005; 7: 901-908
  CrossrefPubMedGoogle Scholar
• 92 Cohen AW, Park DS, Woodman SE, Williams TM, Chandra M, Shirani J, Pereira de SA, Kitsis RN, Russell RG, Weiss LM, Tang B, Jelicks LA, Factor SM, Shtutin V, Tanowitz HB, Lisanti MP. Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts. Am J Physiol Cell Physiol 2003; 284: C457-C474
  CrossrefPubMedGoogle Scholar
• 93 Torres VA, Tapia JC, Rodriguez DA, Parraga M, Lisboa P, Montoya M, Leyton L, Quest AF. Caveolin-1 controls cell proliferation and cell death by suppressing expression of the inhibitor of apoptosis protein survivin. J Cell Sci 2006; 119 (Pt 9) 1812-1823
  CrossrefPubMedGoogle Scholar
• 94 Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem 2002; 277: 8635-8647
  CrossrefPubMedGoogle Scholar
• 95 Fernandez MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, Kurzchalia T, Tebar F, Enrich C, Parton RG, Pol A. Caveolin-1 is essential for liver regeneration. Science 2006; 313 (5793) 1628-1632
  CrossrefPubMedGoogle Scholar
• 96 Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 2001; 293 (5539) 2449-2452
  CrossrefPubMedGoogle Scholar
• 97 Trushina E, Du CJ, Parisi J, McMurray CT. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res 2006; 172: 24-32
  CrossrefPubMedGoogle Scholar
• 98 Augustus AS, Buchanan J, Addya S, Rengo G, Pestell RG, Fortina P, Koch WJ, Bensadoun A, Abel ED, Lisanti MP. Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts. Am J Physiol Heart Circ Physiol 2008; 295: H657-H666
  CrossrefPubMedGoogle Scholar
• 99 Head BP, Patel HH, Roth DM, Lai NC, Niesman IR, Farquhar MG, Insel PA. G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem 2005; 280: 31036-31044
  CrossrefPubMedGoogle Scholar
• 100 Calaghan S, Kozera L, White E. Compartmentalisation of cAMP-dependent signalling by caveolae in the adult cardiac myocyte. J Mol Cell Cardiol 2008; 45: 88-92
  CrossrefPubMedGoogle Scholar
• 101 Cohen AW, Razani B, Schubert W, Williams TM, Wang XB, Iyengar P, Brasaemle DL, Scherer PE, Lisanti MP. Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes 2004; 53: 1261-1270
  CrossrefPubMedGoogle Scholar