Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: Feedback loops, titrated phosphorylations and pharmacological modulation

BMC Systems Biology

Volumn 5, Issue , 2011, Pages

  Wangorsch, Gaby ^a   Butt, Elke ^b   Mark, Regina ^b   Hubertus, Katharina ^b   Geiger, Jörg ^b   Dandekar, Thomas ^a,c   Dittrich, Marcus ^a  

^a UNIVERSITY OF WÜRZBURG   (Germany)

^b Institute of Clinical Biochemistry and Pathobiochemistry   (Germany)

^c EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP;

ARTICLE; BIOLOGICAL MODEL; BIOLOGY; COMPUTER SIMULATION; HUMAN; METABOLISM; METHODOLOGY; PHOSPHORYLATION; SIGNAL TRANSDUCTION; SYSTEMS BIOLOGY; THROMBOCYTE; THROMBOCYTE AGGREGATION; VALIDATION STUDY;

BLOOD PLATELETS; COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; CYCLIC AMP; HUMANS; MODELS, BIOLOGICAL; PHOSPHORYLATION; PLATELET AGGREGATION; SIGNAL TRANSDUCTION; SYSTEMS BIOLOGY;

EID: 80055002192     PISSN: None     EISSN: 17520509     Source Type: Journal    
DOI: 10.1186/1752-0509-5-178     Document Type: Article

References (65)

1. Schwarz UR, Walter U, Eigenthaler M. Taming platelets with cyclic nucleotides. Biochemical pharmacology 2001, 62:1153-1161. 10.1016/S0006-2952(01)00760-2, 11705448.
2. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006, 58:488-520. 10.1124/pr.58.3.5, 16968949.
3. Feijge MA, Ansink K, Vanschoonbeek K, Heemskerk JW. Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3. Biochem Pharmacol 2004, 67:1559-1567. 10.1016/j.bcp.2003.12.028, 15041473.
4. Noe L, Peeters K, Izzi B, Van Geet C, Freson K. Regulators of platelet cAMP levels: clinical and therapeutic implications. Curr Med Chem 2010, 17:2897-2905. 10.2174/092986710792065018, 20858171.
5. Geiger J. Inhibitors of platelet signal transduction as anti-aggregatory drugs. Expert Opin Investig Drugs 2001, 10:865-890. 10.1517/13543784.10.5.865, 11322863.
6. Wang Y, Aguda BD, Friedman A. A continuum mathematical model of endothelial layer maintenance and senescence. Theor Biol Med Model 2007, 4:30. 10.1186/1742-4682-4-30, 1988791, 17692115.
7. Xu Z, Chen N, Kamocka MM, Rosen ED, Alber M. A multiscale model of thrombus development. J R Soc Interface 2008, 5:705-722. 10.1098/rsif.2007.1202, 2607450, 17925274.
8. Swameye I, Muller TG, Timmer J, Sandra O, Klingmuller U. Identification of nucleocytoplasmic cycling as a remote sensor in cellular signaling by databased modeling. Proc Natl Acad Sci USA 2003, 100:1028-1033. 10.1073/pnas.0237333100, 298720, 12552139.
9. Schilling M, Maiwald T, Hengl S, Winter D, Kreutz C, Kolch W, Lehmann WD, Timmer J, Klingmuller U. Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions. Mol Syst Biol 2009, 5:334. 2824492, 20029368.
10. Hsieh MY, Yang S, Raymond-Stinz MA, Edwards JS, Wilson BS. Spatio-temporal modeling of signaling protein recruitment to EGFR. BMC Syst Biol 2010, 4:57. 10.1186/1752-0509-4-57, 2877007, 20459599.
11. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 2002, 298:1241-1245. 10.1126/science.1071914, 12424381.
12. Dittrich M, Birschmann I, Mietner S, Sickmann A, Walter U, Dandekar T. Platelet protein interactions: map, signaling components, and phosphorylation groundstate. Arterioscler Thromb Vasc Biol 2008, 28:1326-1331. 10.1161/ATVBAHA.107.161000, 18451328.
13. Dittrich M, Birschmann I, Pfrang J, Herterich S, Smolenski A, Walter U, Dandekar T. Analysis of SAGE data in human platelets: features of the transcriptome in an anucleate cell. Thromb Haemost 2006, 95:643-651.
14. Eigenthaler M, Nolte C, Halbrugge M, Walter U. Concentration and regulation of cyclic nucleotides, cyclic-nucleotide-dependent protein kinases and one of their major substrates in human platelets. Estimating the rate of cAMP-regulated and cGMP-regulated protein phosphorylation in intact cells. Eur J Biochem 1992, 205:471-481. 10.1111/j.1432-1033.1992.tb16803.x, 1315268.
15. Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res 2003, 39:67-86. 10.1540/jsmr.39.67, 14692693.
16. Butt E, Walter U. Platelet phosphodiesterases. Handbook of experimental pharmacology 1997, 126:219-230.
17. Hines LM, Tabakoff B. Platelet adenylyl cyclase activity: a biological marker for major depression and recent drug use. Biol Psychiatry 2005, 58:955-962. 10.1016/j.biopsych.2005.05.040, 16095566.
18. Parsian A, Todd RD, Cloninger CR, Hoffman PL, Ovchinnikova L, Ikeda H, Tabakoff B. Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clinical Centers. Alcohol Clin Exp Res 1996, 20:745-751. 10.1111/j.1530-0277.1996.tb01681.x, 8800394.
19. Juska A, Farndale RW. Inhibition of human platelet adenylate cyclase activity by adrenaline, thrombin and collagen: analysis and reinterpretation of experimental data. Biochem J 1999, 340(Pt 1):245-253. 1220255, 10391837.
20. Wilson LS, Elbatarny HS, Crawley SW, Bennett BM, Maurice DH. Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions. Proc Natl Acad Sci USA 2008, 105:13650-13655. 10.1073/pnas.0804738105, 2533244, 18757735.
21. Baillie GS. Compartmentalized signalling: spatial regulation of cAMP by the action of compartmentalized phosphodiesterases. FEBS J 2009, 276:1790-1799. 10.1111/j.1742-4658.2009.06926.x, 19243430.
22. Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 2010, 35:91-100. 10.1016/j.tibs.2009.09.007, 19864144.
23. Floreani M, Fossa P, Gessi S, Mosti L, Borea PA, Dorigo P. New milrinone analogues: in vitro study of structure-activity relationships for positive inotropic effect, antagonism towards endogenous adenosine, and inhibition of cardiac type III phosphodiesterase. Naunyn Schmiedebergs Arch Pharmacol 2003, 367:109-118. 10.1007/s00210-002-0675-2, 12595951.
24. Macphee CH, Reifsnyder DH, Moore TA, Lerea KM, Beavo JA. Phosphorylation results in activation of a cAMP phosphodiesterase in human platelets. J Biol Chem 1988, 263:10353-10358.
25. Iwami G, Kawabe J, Ebina T, Cannon PJ, Homcy CJ, Ishikawa Y. Regulation of adenylyl cyclase by protein kinase A. J Biol Chem 1995, 270:12481-12484. 10.1074/jbc.270.21.12481, 7759492.
26. Murthy KS, Zhou H, Makhlouf GM. PKA-dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle. Am J Physiol Cell Physiol 2002, 282:C508-C517.
27. 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. 10.1074/jbc.M807536200, 2673302, 19261611.
28. Chen Y, Harry A, Li J, Smit MJ, Bai X, Magnusson R, Pieroni JP, Weng G, Iyengar R. Adenylyl cyclase 6 is selectively regulated by protein kinase A phosphorylation in a region involved in Galphas stimulation. Proceedings of the National Academy of Sciences of the United States of America 1997, 94:14100-14104. 10.1073/pnas.94.25.14100, 28439, 9391159.
29. Cox DR, Hinkley DV. Theoretical Statistics 1994, New York: Chapman and Hall.
30. Nolte C, Eigenthaler M, Horstrup K, Honig-Liedl P, Walter U. Synergistic phosphorylation of the focal adhesion-associated vasodilator-stimulated phosphoprotein in intact human platelets in response to cGMP- and cAMP-elevating platelet inhibitors. Biochem Pharmacol 1994, 48:1569-1575. 10.1016/0006-2952(94)90201-1, 7980622.
31. Hanson MS, Stephenson AH, Bowles EA, Sridharan M, Adderley S, Sprague RS. Phosphodiesterase 3 is present in rabbit and human erythrocytes and its inhibition potentiates iloprost-induced increases in cAMP. Am J Physiol Heart Circ Physiol 2008, 295:H786-793. 10.1152/ajpheart.00349.2008, 2519193, 18586889.
32. Netherton SJ, Jimmo SL, Palmer D, Tilley DG, Dunkerley HA, Raymond DR, Russell JC, Absher PM, Sage EH, Vernon RB, et al. Altered phosphodiesterase 3-mediated cAMP hydrolysis contributes to a hypermotile phenotype in obese JCR:LA-cp rat aortic vascular smooth muscle cells: implications for diabetes-associated cardiovascular disease. Diabetes 2002, 51:1194-1200. 10.2337/diabetes.51.4.1194, 11916944.
33. Smolenski A, Bachmann C, Reinhard K, Honig-Liedl P, Jarchau T, Hoschuetzky H, Walter U. Analysis and regulation of vasodilator-stimulated phosphoprotein serine 239 phosphorylation in vitro and in intact cells using a phosphospecific monoclonal antibody. J Biol Chem 1998, 273:20029-20035. 10.1074/jbc.273.32.20029, 9685341.
34. Butt E, Abel K, Krieger M, Palm D, Hoppe V, Hoppe J, Walter U. cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets. J Biol Chem 1994, 269:14509-14517.
35. Geiger J, Brandmann T, Hubertus K, Tjahjadi B, Schinzel R, Walter U. A protein phosphorylation-based assay for screening and monitoring of drugs modulating cyclic nucleotide pathways. Anal Biochem 2010, 407:261-269. 10.1016/j.ab.2010.08.006, 20708596.
36. Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J 2008, 31:891-901. 10.1183/09031936.00097107, 18378784.
37. Patrignani P, Di Febbo C, Tacconelli S, Douville K, Guglielmi MD, Horvath RJ, Ding M, Sierra K, Stitham J, Gleim S, et al. Differential association between human prostacyclin receptor polymorphisms and the development of venous thrombosis and intimal hyperplasia: a clinical biomarker study. Pharmacogenet Genomics 2008, 18:611-620. 10.1097/FPC.0b013e328301a774, 18551041.
38. Arehart E, Stitham J, Asselbergs FW, Douville K, MacKenzie T, Fetalvero KM, Gleim S, Kasza Z, Rao Y, Martel L, et al. Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circulation research 2008, 102:986-993. 10.1161/CIRCRESAHA.107.165936, 2793685, 18323528.
39. Omori K, Kotera J. Overview of PDEs and their regulation. Circulation research 2007, 100:309-327. 10.1161/01.RES.0000256354.95791.f1, 17307970.
40. Aktas B, Honig-Liedl P, Walter U, Geiger J. Inhibition of platelet P2Y12 and alpha2A receptor signaling by cGMP-dependent protein kinase. Biochemical pharmacology 2002, 64:433-439. 10.1016/S0006-2952(02)01113-9, 12147294.
41. Witt J, Barisic S, Schumann E, Allgower F, Sawodny O, Sauter T, Kulms D. Mechanism of PP2A-mediated IKK beta dephosphorylation: a systems biological approach. BMC Syst Biol 2009, 3:71. 10.1186/1752-0509-3-71, 2727496, 19607706.
42. van Riel NA. Dynamic modelling and analysis of biochemical networks: mechanism-based models and model-based experiments. Brief Bioinform 2006, 7:364-374. 10.1093/bib/bbl040, 17107967.
43. Maiwald T, Timmer J. Dynamical modeling and multi-experiment fitting with PottersWheel. Bionformatics 2008, 24:2037-2043.
44. Coleman TF, Li AY. An Interior Trust Region Approach for Nonlinear Minimization Subject to Bounds. SIAM Journal on Optimization 1996, 6:418-455.
45. 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. The Journal of biological chemistry 2000, 275:38749-38761.
46. Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 2007, 100:1569-1578. 10.1161/CIRCRESAHA.106.144501, 17556670.
47. Dittrich M, Strassberger V, Fackler M, Tas P, Lewandrowski U, Sickmann A, Walter U, Dandekar T, Birschmann I. Characterization of a novel interaction between vasodilator-stimulated phosphoprotein and Abelson interactor 1 in human platelets: a concerted computational and experimental approach. Arterioscler Thromb Vasc Biol 2010, 30:843-850. 10.1161/ATVBAHA.109.200683, 20110575.
48. Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov 2010, 9:154-169. 10.1038/nrd2957, 20118963.
49. Rao YJ, Xi L. Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts. Acta Pharmacol Sin 2009, 30:1-24. 10.1038/aps.2008.1, 19060915.
50. Pierre S, Eschenhagen T, Geisslinger G, Scholich K. Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov 2009, 8:321-335. 10.1038/nrd2827, 19337273.
51. Lobato EB, Beaver T, Muehlschlegel J, Kirby DS, Klodell C, Sidi A. Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension. Br J Anaesth 2006, 96:317-322. 10.1093/bja/ael009, 16443640.
52. Mackenzie IS, Coughtrie MW, MacDonald TM, Wei L. Antiplatelet drug interactions. J Intern Med 2010, 268:516-529. 10.1111/j.1365-2796.2010.02299.x, 21073556.
53. Yan H, Zhang B, Li S, Zhao Q. A formal model for analyzing drug combination effects and its application in TNF-alpha-induced NFkappaB pathway. BMC Syst Biol 2010, 4:50. 10.1186/1752-0509-4-50, 2873319, 20416113.
54. Geva-Zatorsky N, Dekel E, Cohen AA, Danon T, Cohen L, Alon U. Protein dynamics in drug combinations: a linear superposition of individual-drug responses. Cell 2010, 140:643-651. 10.1016/j.cell.2010.02.011, 20211134.
55. Corbin JD, Beebe SJ, Blackmore PF. cAMP-dependent protein kinase activation lowers hepatocyte cAMP. The Journal of biological chemistry 1985, 260:8731-8735.
56. Gettys TW, Vine AJ, Simonds MF, Corbin JD. Activation of the particulate low Km phosphodiesterase of adipocytes by addition of cAMP-dependent protein kinase. The Journal of biological chemistry 1988, 263:10359-10363.
57. Ball EH, Seth PK, Sanwal BD. Regulatory mechanisms involved in the control of cyclic adenosine 3':5'-monophosphate phosphodiesterases in myoblasts. The Journal of biological chemistry 1980, 255:2962-2968.
58. Alvarez R, Sette C, Yang D, Eglen RM, Wilhelm R, Shelton ER, Conti M. Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3. Mol Pharmacol 1995, 48:616-622.
59. Ahlstrom M, Lamberg-Allardt C. Rapid protein kinase A--mediated activation of cyclic AMP-phosphodiesterase by parathyroid hormone in UMR-106 osteoblast-like cells. J Bone Miner Res 1997, 12:172-178. 10.1359/jbmr.1997.12.2.172, 9041048.
60. Pozuelo Rubio M, 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, 392:163-172. 10.1042/BJ20051103, 1317675, 16153182.
61. Aktas B, Utz A, Hoenig-Liedl P, Walter U, Geiger J. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies. Stroke 2003, 34:764-769. 10.1161/01.STR.0000056527.34434.59, 12624305.
62. Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur J Pharmacol 1998, 351:235-246. 10.1016/S0014-2999(98)00305-7, 9687008.
63. Poppe H, Rybalkin SD, Rehmann H, Hinds TR, Tang XB, Christensen AE, Schwede F, Genieser HG, Bos JL, Doskeland SO, et al. Cyclic nucleotide analogs as probes of signaling pathways. Nat Methods 2008, 5:277-278. 10.1038/nmeth0408-277, 18376388.
64. Schmidt K, Schrammel A, Koesling D, Mayer B. Molecular mechanisms involved in the synergistic activation of soluble guanylyl cyclase by YC-1 and nitric oxide in endothelial cells. Mol Pharmacol 2001, 59:220-224.
65. Wu CC, Ko FN, Kuo SC, Lee FY, Teng CM. YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. Br J Pharmacol 1995, 116:1973-1978. 1908948, 8640334.