Signalling by protein phosphatases and drug development: A systems-centred view

FEBS Journal

Volumn 280, Issue 2, 2013, Pages 751-765

  Nguyen, Lan K ^a   Matallanas, David ^a   Croucher, David R ^a   Von Kriegsheim, Alexander ^a   Kholodenko, Boris N ^a  

^a UNIVERSITY COLLEGE DUBLIN   (Ireland)

Author keywords

computational modelling; drug discovery; drug intervention; MAP kinase; phosphatase targeted therapies; phosphatases; SHP2; signalling cascades; spatiotemporal dynamics; systems biology

Indexed keywords

BIDENTATE DIFLUOROMETHYLPHOSPHONIC ACID; CELL DIVISION CYCLE 14 HOMOLOG; CELL DIVISION CYCLE 25 HOMOLOG; DUAL SPECIFICITY PHOSPHATASE; ERTIPROTAFIB; EYES ABSENT HOMOLOG 1/3; MITOGEN ACTIVATED PROTEIN KINASE; ORTHOVANADIC ACID; PHOSPHATASE OF REGENERATING LIVER 3; PHOSPHOPROTEIN PHOSPHATASE; PROTEIN PHOSPHATASE TYPE 2A; PROTEIN SERINE THREONINE PHOSPHATASE; PROTEIN TYROSINE PHOSPHATASE; PROTEIN TYROSINE PHOSPHATASE 1B; PROTEIN TYROSINE PHOSPHATASE 1B INHIBITOR; PROTEIN TYROSINE PHOSPHATASE SHP 2; RAF PROTEIN; RAS PROTEIN; TRODUSQUEMINE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; BREAST CANCER; DIABETES MELLITUS; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INACTIVATION; ENZYME MECHANISM; ENZYME PHOSPHORYLATION; ENZYME REGULATION; ENZYME SPECIFICITY; ENZYME SUBSTRATE COMPLEX; ENZYME SUBUNIT; FEEDBACK SYSTEM; GAIN OF FUNCTION MUTATION; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MATHEMATICAL MODEL; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN DEPHOSPHORYLATION; PROTEIN EXPRESSION; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SIMULATION; TRANSCRIPTION REGULATION;

DRUG DISCOVERY; ENZYME INHIBITORS; HUMANS; PHOSPHOPROTEIN PHOSPHATASES; SIGNAL TRANSDUCTION; SYSTEMS BIOLOGY;

EID: 84872784481     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/j.1742-4658.2012.08522.x     Document Type: Review

References (99)

1. Malumbres M, &, Barbacid M, (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9, 153-166.
2. Waltermann C, &, Klipp E, (2010) Signal integration in budding yeast. Biochem Soc Trans 38, 1257-1264.
3. Efeyan A, &, Sabatini DM, (2010) mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 22, 169-176.
4. Brown GC, &, Kholodenko BN, (1999) Spatial gradients of cellular phospho-proteins. FEBS Lett 457, 452-454.
5. Heinrich R, Neel BG, &, Rapoport TA, (2002) Mathematical models of protein kinase signal transduction. Mol Cell 9, 957-970.
6. Reynolds AR, Tischer C, Verveer PJ, Rocks O, &, Bastiaens PI, (2003) EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation. Nat Cell Biol 5, 447-453.
7. Montagner A, Yart A, Dance M, Perret B, Salles JP, &, Raynal P, (2005) A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J Biol Chem 280, 5350-5360.
8. Stoker AW, (2005) Protein tyrosine phosphatases and signalling. J Endocrinol 185, 19-33.
9. Asante-Appiah E, &, Kennedy BP, (2003) Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am J Physiol 284, E663-E670.
10. Alonso A, Sasin J, Bottini N, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, &, Mustelin T, (2004) Protein tyrosine phosphatases in the human genome. Cell 117, 699-711.
11. Van Kanegan MJ, Adams DG, Wadzinski BE, &, Strack S, (2005) Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt. J Biol Chem 280, 36029-36036.
12. Shi Y, (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139, 468-484.
13. Schaeffer HJ, &, Weber MJ, (1999) Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19, 2435-2444.
14. Kolch W, (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351, 289-305.
15. Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S, &, Pouyssegur J, (1993) Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci USA 90, 8319-8323.
16. Marshall CJ, (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179-185.
17. Tombes RM, Auer KL, Mikkelsen R, Valerie K, Wymann MP, Marshall CJ, McMahon M, &, Dent P, (1998) The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic. Biochem J 330, 1451-1460.
18. Nakakuki T, Birtwistle MR, Saeki Y, Yumoto N, Ide K, Nagashima T, Brusch L, Ogunnaike BA, Okada-Hatakeyama M, &, Kholodenko BN, (2010) Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell 141, 884-896.
19. Kholodenko BN, Demin OV, Moehren G, &, Hoek JB, (1999) Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem 274, 30169-30181.
20. Hornberg JJ, Bruggeman FJ, Binder B, Geest CR, de Vaate AJ, Lankelma J, Heinrich R, &, Westerhoff HV, (2005) Principles behind the multifarious control of signal transduction. ERK phosphorylation and kinase/phosphatase control. FEBS J 272, 244-258.
21. Asthagiri AR, &, Lauffenburger DA, (2001) A computational study of feedback effects on signal dynamics in a mitogen-activated protein kinase (MAPK) pathway model. Biotechnol Prog 17, 227-239.
22. Kholodenko BN, (2000) Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur J Biochem 267, 1583-1588.
23. Bhalla US, &, Iyengar R, (1999) Emergent properties of networks of biological signaling pathways. Science 283, 381-387.
24. Yarden Y, &, Sliwkowski MX, (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2, 127-137.
25. Casci T, Vinos J, &, Freeman M, (1999) Sprouty, an intracellular inhibitor of Ras signaling. Cell 96, 655-665.
26. Hackel PO, Gishizky M, &, Ullrich A, (2001) Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biol Chem 382, 1649-1662.
27. Sun H, Charles CH, Lau LF, &, Tonks NK, (1993) MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75, 487-493.
28. Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, Keenan ID, Dickinson RJ, Storey KG, &, Keyse SM, (2008) Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J 412, 287-298.
29. Reference withdrawn.
30. Owens DM, &, Keyse SM, (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203-3213.
31. Yoon S, &, Seger R, (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24, 21-44.
32. Legewie S, Herzel H, Westerhoff HV, &, Bluthgen N, (2008) Recurrent design patterns in the feedback regulation of the mammalian signalling network. Mol Syst Biol 4, 190.
33. Bhalla US, Ram PT, &, Iyengar R, (2002) MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018-1023.
34. Bluthgen N, Legewie S, Kielbasa SM, Schramme A, Tchernitsa O, Keil J, Solf A, Vingron M, Schafer R, Herzel H, et al. (2009) A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts. FEBS J 276, 1024-1035.
35. Kholodenko BN, (2006) Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol 7, 165-176.
36. Hilioti Z, Sabbagh W Jr, Paliwal S, Bergmann A, Goncalves MD, Bardwell L, &, Levchenko A, (2008) Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr Biol 18, 1700-1706.
37. Lipkow K, Andrews SS, &, Bray D, (2005) Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli. J Bacteriol 187, 45-53.
38. Kholodenko BN, (2002) MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends Cell Biol 12, 173-177.
39. Kalab P, Weis K, &, Heald R, (2002) Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 295, 2452-2456.
40. Maeder CI, Hink MA, Kinkhabwala A, Mayr R, Bastiaens PI, &, Knop M, (2007) Spatial regulation of Fus3 MAP kinase activity through a reaction-diffusion mechanism in yeast pheromone signalling. Nat Cell Biol 9, 1319-1326.
41. Yudushkin IA, Schleifenbaum A, Kinkhabwala A, Neel BG, Schultz C, &, Bastiaens PI, (2007) Live-cell imaging of enzyme-substrate interaction reveals spatial regulation of PTP1B. Science 315, 115-119.
42. Fuller BG, Lampson MA, Foley EA, Rosasco-Nitcher S, Le KV, Tobelmann P, Brautigan DL, Stukenberg PT, &, Kapoor TM, (2008) Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature 453, 1132-1136.
43. Moseley JB, Mayeux A, Paoletti A, &, Nurse P, (2009) A spatial gradient coordinates cell size and mitotic entry in fission yeast. Nature 459, 857-860.
44. Munoz-Garcia J, &, Kholodenko BN, (2010) Signalling over a distance: gradient patterns and phosphorylation waves within single cells. Biochem Soc Trans 38, 1235-1241.
45. Munoz-Garcia J, Neufeld Z, &, Kholodenko BN, (2009) Positional information generated by spatially distributed signaling cascades. PLoS Comput Biol 5, e1000330.
46. Araujo RP, Liotta LA, &, Petricoin EF, (2007) Proteins, drug targets and the mechanisms they control: the simple truth about complex networks. Nat Rev Drug Discov 6, 871-880.
47. Jiang ZX, &, Zhang ZY, (2008) Targeting PTPs with small molecule inhibitors in cancer treatment. Cancer Metastasis Rev 27, 263-272.
48. Barr AJ, (2010) Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor development. Future Med Chem 2, 1563-1576.
49. Scott LM, Lawrence HR, Sebti SM, Lawrence NJ, &, Wu J, (2010) Targeting protein tyrosine phosphatases for anticancer drug discovery. Curr Pharm Des 16, 1843-1862.
50. Perrotti D, &, Neviani P, (2008) Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. Cancer Metastasis Rev 27, 159-168.
51. Tonks NK, (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7, 833-846.
52. MacKeigan JP, Murphy LO, &, Blenis J, (2005) Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol 7, 591-600.
53. Byon JC, Kusari AB, &, Kusari J, (1998) Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem 182, 101-108.
54. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, et al. (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544-1548.
55. Wiener JR, Kerns BJ, Harvey EL, Conaway MR, Iglehart JD, Berchuck A, &, Bast RC Jr, (1994) Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J Natl Cancer Inst 86, 372-378.
56. Zhu S, Bjorge JD, &, Fujita DJ, (2007) PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation. Cancer Res 67, 10129-10137.
57. Sun JP, Fedorov AA, Lee SY, Guo XL, Shen K, Lawrence DS, Almo SC, &, Zhang ZY, (2003) Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem 278, 12406-12414.
58. Boutselis IG, Yu X, Zhang ZY, &, Borch RF, (2007) Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug. J Med Chem 50, 856-864.
59. Erbe DV, Wang S, Zhang YL, Harding K, Kung L, Tam M, Stolz L, Xing Y, Furey S, Qadri A, et al. (2005) Ertiprotafib improves glycemic control and lowers lipids via multiple mechanisms. Mol Pharmacol 67, 69-77.
60. Roitman MF, Wescott S, Cone JJ, McLane MP, &, Wolfe HR, (2010) MSI-1436 reduces acute food intake without affecting dopamine transporter activity. Pharmacol Biochem Behav 97, 138-143.
61. Imhof D, Wavreille AS, May A, Zacharias M, Tridandapani S, &, Pei D, (2006) Sequence specificity of SHP-1 and SHP-2 Src homology 2 domains. Critical roles of residues beyond the pY+3 position. J Biol Chem 281, 20271-20282.
62. Lazzara MJ, Lane K, Chan R, Jasper PJ, Yaffe MB, Sorger PK, Jacks T, Neel BG, &, Lauffenburger DA, (2010) Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations. Cancer Res 70, 3843-3850.
63. Tartaglia M, &, Gelb BD, (2005) Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet 48, 81-96.
64. Naing A, Reuben JM, Camacho LH, Gao H, Lee BN, Cohen EN, Verschraegen C, Stephen S, Aaron J, Hong D, et al. (2011) Phase I dose escalation study of sodium stibogluconate (SSG), a protein tyrosine phosphatase inhibitor, combined with interferon alpha for patients with solid tumors. J Cancer 2, 81-89.
65. Moorhead GB, De Wever V, Templeton G, &, Kerk D, (2009) Evolution of protein phosphatases in plants and animals. Biochem J 417, 401-409.
66. Pereira SR, Vasconcelos VM, &, Antunes A, (2011) The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins. Crit Rev Toxicol 41, 83-110.
67. Sablina AA, Hector M, Colpaert N, &, Hahn WC, (2010) Identification of PP2A complexes and pathways involved in cell transformation. Cancer Res 70, 10474-10484.
68. Ruediger R, Pham HT, &, Walter G, (2001) Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene 20, 1892-1899.
69. Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, Croce CM, Barbanti-Brodano G, Russo G, &, Negrini M, (2000) Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195.
70. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, et al. (2005) The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 8, 355-368.
71. Kovacech B, Kontsekova E, Zilka N, Novak P, Skrabana R, Filipcik P, Iqbal K, &, Novak M, (2007) A novel monoclonal antibody DC63 reveals that inhibitor 1 of protein phosphatase 2A is preferentially nuclearly localised in human brain. FEBS Lett 581, 617-622.
72. Corcoran NM, Martin D, Hutter-Paier B, Windisch M, Nguyen T, Nheu L, Sundstrom LE, Costello AJ, &, Hovens CM, (2010) Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J Clin Neurosci 17, 1025-1033.
73. Singh M, Cugati G, Singh P, &, Singh AK, (2011) Fingolimod: the first oral drug approved by Food and Drug Administration; a breakthrough in treatment of multiple sclerosis. J Pharm Bioallied Sci 3, 460-461.
74. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, Liu S, Trotta R, Muthusamy N, Gambacorti-Passerini C, et al. (2007) FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 117, 2408-2421.
75. Almo SC, Bonanno JB, Sauder JM, Emtage S, Dilorenzo TP, Malashkevich V, Wasserman SR, Swaminathan S, Eswaramoorthy S, Agarwal R, et al. (2007) Structural genomics of protein phosphatases. J Struct Funct Genomics 8, 121-140.
76. Roy J, &, Cyert MS, (2009) Cracking the phosphatase code: docking interactions determine substrate specificity. Sci Signal 2, re9.
77. Slupe AM, Merrill RA, &, Strack S, (2011) Determinants for substrate specificity of protein phosphatase 2A. Enzyme Res 2011, 398751.
78. Lechward K, Awotunde OS, Swiatek W, &, Muszynska G, (2001) Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochim Pol 48, 921-933.
79. Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S, Poletti F, Rimessi A, et al. (2011) Protein kinases and phosphatases in the control of cell fate. Enzyme Res 2011, 329098.
80. Janssens V, &, Goris J, (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353, 417-439.
81. Eichhorn PJ, Creyghton MP, &, Bernards R, (2009) Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795, 1-15.
82. Abraham D, Podar K, Pacher M, Kubicek M, Welzel N, Hemmings BA, Dilworth SM, Mischak H, Kolch W, &, Baccarini M, (2000) Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J Biol Chem 275, 22300-22304.
83. Ory S, Zhou M, Conrads TP, Veenstra TD, &, Morrison DK, (2003) Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13, 1356-1364.
84. Letourneux C, Rocher G, &, Porteu F, (2006) B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J 25, 727-738.
85. Ugi S, Imamura T, Ricketts W, &, Olefsky JM, (2002) Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. Mol Cell Biol 22, 2375-2387.
86. Eichhorn PJ, Creyghton MP, Wilhelmsen K, van Dam H, &, Bernards R, (2007) A RNA interference screen identifies the protein phosphatase 2A subunit PR55γ as a stress-sensitive inhibitor of c-SRC. PLoS Genet 3, e218.
87. Witt J, Barisic S, Schumann E, Allgower F, Sawodny O, Sauter T, &, Kulms D, (2009) Mechanism of PP2A-mediated IKKβ dephosphorylation: a systems biological approach. BMC Syst Biol 3, 71.
88. Harvey SL, Enciso G, Dephoure NE, Gygi SP, Gunawardena J, &, Kellogg DR, (2011) A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast. Mol Biol Cell 22, 3595-3608.
89. Glatter T, Wepf A, Aebersold R, &, Gstaiger M, (2009) An integrated workflow for charting the human interaction proteome: insights into the PP2A system. Mol Syst Biol 5, 237.
90. Cho CR, Labow M, Reinhardt M, van Oostrum J, &, Peitsch MC, (2006) The application of systems biology to drug discovery. Curr Opin Chem Biol 10, 294-302.
91. Belardinelli L, Shryock JC, &, Fraser H, (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 92 (Suppl. 4), iv6-iv14.
92. Noble D, &, Noble PJ, (2006) Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart 92 (Suppl. 4), iv1-iv5.
93. Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin I, et al. (2009) Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res 69, 6713-6720.
94. Peng H, Wen J, Li H, Chang J, &, Zhou X, (2011) Drug inhibition profile prediction for NFκB pathway in multiple myeloma. PLoS One 6, e14750.
95. Kim DH, Rho K, &, Kim S, (2009) A theoretical model for p53 dynamics: identifying optimal therapeutic strategy for its activation and stabilization. Cell Cycle 8, 3707-3716.
96. Borisov NM, Markevich NI, Hoek JB, &, Kholodenko BN, (2005) Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity. Biophys J 89, 951-966.
97. Borisov NM, Markevich NI, Hoek JB, &, Kholodenko BN, (2006) Trading the micro-world of combinatorial complexity for the macro-world of protein interaction domains. Biosystems 83, 152-166.
98. Conzelmann H, Saez-Rodriguez J, Sauter T, Kholodenko BN, &, Gilles ED, (2006) A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks. BMC Bioinformatics 7, 34.
99. Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, &, Kholodenko BN, (2007) Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol 3, 144.