The gastrin and cholecystokinin receptors mediated signaling network: a scaffold for data analysis and new hypotheses on regulatory mechanisms

BMC Systems Biology

Astrid Lægreid⁴  Martin Kuiper²  Liv Thommesen³  Torunn Bruland¹  Anaïs Baudot⁵  Konika Chawla²  Åsmund Flobak¹  Sushil Tripathi¹ 

[1] Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, N-7489, Norway;Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim, N-7491, Norway;Department of Technology, Sør-Trøndelag University College, Trondheim, N-7004, Norway;Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, N-7489, Norway;I2M, Marseilles Institute of Mathematics CNRS - AMU, Case 907, Marseille, 13288, Cedex 9, France

关键词: Gastrin;    Signaling pathway;    Protein-protein interaction;    Network;    Modules;    Model;    Map;    Cholecystokinin receptor;   

Others  :  1230649
DOI  :  10.1186/s12918-015-0181-z

 received in 2013-03-09, accepted in 2015-06-16,  发布年份 2015

【 摘 要 】

Background

The gastrointestinal peptide hormones cholecystokinin and gastrin exert their biological functions via cholecystokinin receptors CCK1R and CCK2R respectively. Gastrin, a central regulator of gastric acid secretion, is involved in growth and differentiation of gastric and colonic mucosa, and there is evidence that it is pro-carcinogenic. Cholecystokinin is implicated in digestion, appetite control and body weight regulation, and may play a role in several digestive disorders.

Results

We performed a detailed analysis of the literature reporting experimental evidence on signaling pathways triggered by CCK1R and CCK2R, in order to create a comprehensive map of gastrin and cholecystokinin-mediated intracellular signaling cascades. The resulting signaling map captures 413 reactions involving 530 molecular species, and incorporates the currently available knowledge into one integrated signaling network. The decomposition of the signaling map into sub-networks revealed 18 modules that represent higher-level structures of the signaling map. These modules allow a more compact mapping of intracellular signaling reactions to known cell behavioral outcomes such as proliferation, migration and apoptosis. The integration of large-scale protein-protein interaction data to this literature-based signaling map in combination with topological analyses allowed us to identify 70 proteins able to increase the compactness of the map. These proteins represent experimentally testable hypotheses for gaining new knowledge on gastrin- and cholecystokinin receptor signaling. The CCKR map is freely available both in a downloadable, machine-readable SBML-compatible format and as a web resource through PAYAO (http://sblab.celldesigner.org:18080/Payao11/bin/).

Conclusion

We have demonstrated how a literature-based CCKR signaling map together with its protein interaction extensions can be analyzed to generate new hypotheses on molecular mechanisms involved in gastrin- and cholecystokinin-mediated regulation of cellular processes.

【 授权许可】

   
2015 Tripathi et al.

【 图 表 】

Figure 4.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

【 参考文献 】

• [1]Rehfeld JF: The New Biology of Gastrointestinal Hormones. Physiol Rev 1998, 78(4):1087-108.
• [2]Watson SA, Grabowska AM, El-Zaatari M, Takhar A: Gastrin - active participant or bystander in gastric carcinogenesis? Nat Rev Cancer 2006, 6(12):936-46.
• [3]Little TJ, Horowitz M, Feinle-Bisset C: Role of cholecystokinin in appetite control and body weight regulation. Obes Rev 2005, 6(4):297-306.
• [4]Saluja AK, Saluja M, Printz H, Zavertnik A, Sengupta A, Steer ML: Experimental pancreatitis is mediated by low-affinity cholecystokinin receptors that inhibit digestive enzyme secretion. Proc Natl Acad Sci U S A 1989, 86:8968-71.
• [5]Gukovsky I, Cheng JH, Nam KJ, Lee OT, Lugea A, Fischer L, Penninger JM, Pandol SJ, Gukovskaya AS: Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gastroenterology 2004, 126:554-66.
• [6]Dabrowski A, Grady T, Logsdon CD, Williams JA: Jun kinases are rapidly activated by cholecystokinin in rat pancreas both in vitro and in vivo. J Biol Chem 1996, 271:5686-90.
• [7]Gibbs J, Young RC, Smith GP: Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973, 84:488-95.
• [8]Witkamp RF: Current and future drug targets in weight management. Pharm Res 2011, 28:1792-818.
• [9]Varga G, Bálint A, Burghardt B, D'Amato M: Involvement of endogenous CCK and CCK1 receptors in colonic motor function. Br J Pharmacol 2004, 141:1275-84.
• [10]Dufresne M, Seva C, Fourmy D: Cholecystokinin and gastrin receptors. Physiol Rev 2006, 86(3):805-47.
• [11]Cawston EE, Miller LJ: Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor. Br J Pharmacol 2010, 159(5):1009-21.
• [12]Konturek PC, Konturek SJ, Brzozowski T: Helicobacter pylori infection in gastric cancerogenesis. J Physiol Pharmacol 2009, 60(3):3-21.
• [13]Matysiak-Budnik T, Mégraud F: Helicobacter pylori infection and gastric cancer. Eur J Cancer 2006, 42(6):708-16.
• [14]Croft D, O'Kelly G, Wu G, Haw R, Gillespie M, Matthews L, Caudy M, Garapati P, Gopinath G, Jassal B, et al.: Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res 2011, 39(Database issue):D691-7.
• [15]Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M: KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 2012, 40(D1):D109-14.
• [16]Kaizu K, Ghosh S, Matsuoka Y, Moriya H, Shimizu-Yoshida Y, Kitano H: A comprehensive molecular interaction map of the budding yeast cell cycle. Mol Syst Biol 2010, 6:415.
• [17]Gloaguen P, Crépieux P, Heitzler D, Poupon A, Reiter E: Mapping the follicle-stimulating hormone-induced signalling networks. Front Endocrinol 2011, 2:45.
• [18]Oda K, Matsuoka Y, Funahashi A, Kitano H: A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 2005, 1:2005.0010.
• [19]Calzone L, Gelay A, Zinovyev A, Radvanyi F, Barillot E: A comprehensive modular map of molecular interactions in RB/E2F pathway. Mol Syst Biol 2008, 4:173.
• [20]Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, Lemieux S, Perreault C, Roux PP, Kitano H: A comprehensive map of the mTOR signaling network. Mol Syst Biol 2010, 6:453.
• [21]Fink MY, Pincas H, Choi SG, Nudelman G, Sealfon SC: Research Resource: Gonadotropin-Releasing Hormone Receptor-Mediated Signaling Network in L beta T2 Cells: A Pathway-Based Web-Accessible Knowledgebase. Mol Endocrinol 2010, 24(9):1863-71.
• [22]Mizuno S, Iijima R, Ogishima S, Kikuchi M, Matsuoka Y, Ghosh S, Miyamoto T, Miyashita A, Kuwano R, Tanaka H: AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease. BMC Syst Biol 2012, 6:52. BioMed Central Full Text
• [23]Patil S, Pincas H, Seto J, Nudelman G, Nudelman I, Sealfon SC: Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase. BMC Syst Biol 2010, 4:137. BioMed Central Full Text
• [24]Raza S, McDerment N, Lacaze PA, Robertson K, Watterson S, Chen Y, Chisholm M, Eleftheriadis G, Monk S, O'Sullivan M, et al.: Construction of a large scale integrated map of macrophage pathogen recognition and effector systems. BMC Syst Biol 2010, 4:63. BioMed Central Full Text
• [25]Zhong J, Sharma J, Raju R, Palapetta SM, Prasad TS, Huang TC, Yoda A, Tyner JW, van Bodegom D, Weinstock DM, et al.: TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling. Database 2014, 2014:bau007.
• [26]Subbannayya Y, Anuja K, Advani J, Ojha UK, Nanjappa V, George B, Sonawane A, Kumar RV, Ramaswamy G, Pandey A, et al.: A network map of the gastrin signaling pathway. J Cell Commun Signal 2014, 8(2):165-70.
• [27]Zinovyev A, Viara E, Calzone L, Barillot E: BiNoM: a Cytoscape plugin for manipulating and analyzing biological networks. Bioinformatics 2008, 24(6):876-7.
• [28]Glaab E, Baudot A, Krasnogor N, Valencia A: Extending pathways and processes using molecular interaction networks to analyse cancer genome data. BMC Bioinformatics 2010, 11:597. BioMed Central Full Text
• [29]Novere NL, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, Demir E, Wegner K, Aladjem MI, Wimalaratne SM, et al.: The systems biology graphical notation. Nat Biotech 2009, 27(8):735-41.
• [30]Kitano H, Funahashi A, Matsuoka Y, Oda K: Using process diagrams for the graphical representation of biological networks. Nat Biotechnol 2005, 23(8):961-6.
• [31]Novere NL, Finney A, Hucka M, Bhalla US, Campagne F, Collado-Vides J, Crampin EJ, Halstead M, Klipp E, Mendes P, et al.: Minimum information requested in the annotation of biochemical models (MIRIAM). Nat Biotech 2005, 23(12):1509-15.
• [32]Frisch M, Klocke B, Haltmeier M, Frech K: LitInspector: literature and signal transduction pathway mining in PubMed abstracts. Nucleic Acids Res 2009, 37(suppl 2):W135-40.
• [33]Hoffmann R, Valencia A: A gene network for navigating the literature. Nat Genet 2004, 36(7):664.
• [34]Matsuoka Y, Ghosh S, Kikuchi N, Kitano H: Payao: a community platform for SBML pathway model curation. Bioinformatics 2010, 26(10):1381-3.
• [35]Mi H, Thomas P: PANTHER pathway: an ontology-based pathway database coupled with data analysis tools. Methods Mol Biol 2009, 563:123-40.
• [36]Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T: Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 2011, 27(3):431-2.
• [37]Assenov Y, Ramirez F, Schelhorn SE, Lengauer T, Albrecht M: Computing topological parameters of biological networks. Bioinformatics 2008, 24(2):282-4.
• [38]Souiai O, Becker E, Prieto C, Benkahla A, De Las Rivas J, Brun C: Functional integrative levels in the human interactome recapitulate organ organization. PLoS One 2011, 6(7):e22051.
• [39]Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M, Roques BP: International Union of Pharmacology. XXI. Structure, Distribution, and Functions of Cholecystokinin Receptors. Pharmacol Rev 1999, 51(4):745-81.
• [40]Christophe J: Pancreatic tumoral cell line AR42J: an amphicrine model. Am J Physiol 1994, 266(6):G963-71.
• [41]Dabrowski A, VanderKuur JA, CarterSu C, Williams JA: Cholecystokinin stimulates formation of Shc-Grb2 complex in rat pancreatic acinar cells through a protein kinase C-dependent mechanism. J Biol Chem 1996, 271(43):27125-9.
• [42]Dabrowski A, Groblewski GE, Schafer C, Guan KL, Williams JA: Cholecystokinin and EGF activate a MAPK cascade by different mechanisms in rat pancreatic acinar cells. Am J Physiol Cell Physiol 1997, 273(5):C1472-9.
• [43]Sabbatini ME, Bi Y, Ji B, Ernst SA, Williams JA: CCK activates RhoA and Rac1 differentially through Gα13 and Gαq in mouse pancreatic acini. Am J Physiol Cell Physiol 2010, 298(3):C592-601.
• [44]Duan RD, Williams JA: Cholecystokinin rapidly activates mitogen-activated protein kinase in rat pancreatic acini. Am J Physiol Gastrointest Liver Physiol 1994, 267(3):G401-8.
• [45]Paillasse MR, de Medina P, Amouroux G, Mhamdi L, Poirot M, Silvente-Poirot S: Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion. J Lipid Res 2009, 50(11):2203-11.
• [46]Sancho V, Berna MJ, Thill M, Jensen RT: PKCθ activation in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors is needed for stimulation of numerous important cellular signaling cascades. Biochim Biophys Acta 2011, 1813(12):2145-56.
• [47]Quattrone A, Dewaele B, Wozniak A, Bauters M, Vanspauwen V, Floris G, Schoffski P, Chibon F, Coindre JM, Sciot R, et al.: Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumours pathogenesis. J Pathol 2012, 228(4):565-74.
• [48]Wu V, Yang M, McRoberts JA, Ren J, Seensalu R, Zeng N, Dagrag M, Birnbaumer M, Walsh JH: First intracellular loop of the human cholecystokinin-A receptor is essential for cyclic AMP signaling in transfected HEK-293 cells. J Biol Chem 1997, 272:9037-42.
• [49]Le Page SL, Bi Y, Williams JA: CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells. Am J Physiol Cell Physiol 2003, 285:C1197-206.
• [50]Moustafa A, Sakamoto KQ, Habara Y: A fundamental role for NO-PLC signaling pathway in mediating intracellular Ca2+ oscillation in pancreatic acini. Nitric Oxide Biol Chem 2011, 24:139-50.
• [51]Cordelier P, Estève JP, Rivard N, Marletta M, Vaysse N, Susini C, Buscail L: The activation of neuronal NO synthase is mediated by G-protein betagamma subunit and the tyrosine phosphatase SHP-2. FASEB J 1999, 13:2037-50.
• [52]Thorn P, Gerasimenko O, Petersen OH: Cyclic ADP-ribose regulation of ryanodine receptors involved in agonist evoked cytosolic Ca2+ oscillations in pancreatic acinar cells. EMBO J 1994, 13:2038-43.
• [53]Cosker F, Cheviron N, Yamasaki M, Menteyne A, Lund FE, Moutin M-J, Galione A, Cancela J-M: The ecto-enzyme CD38 is a nicotinic acid adenine dinucleotide phosphate (NAADP) synthase that couples receptor activation to Ca2+ mobilization from lysosomes in pancreatic acinar cells. J Biol Chem 2010, 285:38251-9.
• [54]Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, K-t C, et al.: NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 2009, 459:596-600.
• [55]Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA: Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo. Mol Biol Cell 2008, 19(1):198-206.
• [56]Lankisch TO, Nozu F, Owyang C, Tsunoda Y: High-affinity cholecystokinin type A receptor/cytosolic phospholipase A2 pathways mediate Ca2+ oscillations via a positive feedback regulation by calmodulin kinase in pancreatic acini. Eur J Cell Biol 1999, 78(9):632-41.
• [57]Yoshida H, Nozu F, Lankisch TO, Mitamura K, Owyang C, Tsunoda Y: A possible role for Ca(2+)/calmodulin-dependent protein kinase IV during pancreatic acinar stimulus-secretion coupling. Biochim Biophys Acta 2000, 1497(1):155-67.
• [58]Sinclair NF, Ai W, Raychowdhury R, Bi M, Wang TC, Koh TJ, McLaughlin JT: Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 2004, 286(6):G992-9.
• [59]Miyazaki Y, Shinomura Y, Tsutsui S, Zushi S, Higashimoto Y, Kanayama S, Higashiyama S, Taniguchi N, Matsuzawa Y: Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor. Gastroenterology 1999, 116(1):78-89.
• [60]Sturany S, Van Lint J, Gilchrist A, Vandenheede JR, Adler G, Seufferlein T: Mechanism of Activation of Protein Kinase D2(PKD2) by the CCKB/Gastrin Receptor. J Biol Chem 2002, 277(33):29431-6.
• [61]Yassin RR, Little KM: Early signalling mechanism in colonic epithelial cell response to gastrin. Biochem J 1995, 311(Pt 3):945-50.
• [62]He H, Shulkes A, Baldwin GS: PAK1 interacts with beta-catenin and is required for the regulation of the beta-catenin signalling pathway by gastrins. Biochim Biophys Acta 2008, 1783(10):1943-54.
• [63]Mishra P, Senthivinayagam S, Rana A, Rana B: Glycogen Synthase Kinase-3beta regulates Snail and beta-catenin during gastrin-induced migration of gastric cancer cells. J Mol Signal 2010, 5:9. BioMed Central Full Text
• [64]He H, Baldwin GS: Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins. Int J Biochem Cell Biol 2008, 40(10):2018-22.
• [65]He H, Yim M, Liu KH, Cody SC, Shulkes A, Baldwin GS: Involvement of G proteins of the Rho family in the regulation of Bcl-2-like protein expression and caspase 3 activation by Gastrins. Cell Signal 2008, 20(1):83-93.
• [66]Guo Y-S, Cheng J-Z, Jin G-F, Gutkind JS, Hellmich MR, Townsend CM: Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. J Biol Chem 2002, 277:48755-63.
• [67]von Blume J, Knippschild U, Dequiedt F, Giamas G, Beck A, Auer A, Van Lint J, Adler G, Seufferlein T: Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. EMBO J 2007, 26(22):4619-33.
• [68]Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003, 13(11):2498-504.
• [69]Seva C, Kowalski-Chauvel A, Daulhac L, Barthez C, Vaysse N, Pradayrol L: Wortmannin-Sensitive Activation of p70S6-Kinase and MAP-Kinase by the G Protein-Coupled Receptor, G/CCKB. Biochem Biophys Res Commun 1997, 238(1):202-6.
• [70]Kikani CK, Dong LQ, Liu F: “New”-clear functions of PDK1: beyond a master kinase in the cytosol? J Cell Biochem 2005, 96(6):1157-62.
• [71]Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC, Wolfe MM, Baker KM, Pestell RG, Rana B: Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene 2004, 23(20):3689-99.
• [72]Steigedal TS, Bruland T, Misund K, Thommesen L, Laegreid A: Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fos gene expression. Am J Physiol Gastrointest Liver Physiol 2007, 292(4):G1062-9.
• [73]Dehez S, Daulhac L, Kowalski-Chauvel A, Fourmy D, Pradayrol L, Seva C: Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca2+ and Src-dependent mechanisms. FEBS Lett 2001, 496(1):25-30.
• [74]Dehez S, Bierkamp C, Kowalski-Chauvel A, Daulhac L, Escrieut C, Susini C, Pradayrol L, Fourmy D, Seva C: c-Jun NH2-terminal Kinase Pathway in Growth-promoting Effect of the G Protein-coupled Receptor Cholecystokinin B Receptor: A Protein Kinase C/Src-dependent-Mechanism. Cell Growth Differ 2002, 13(8):375-85.
• [75]Stepan VM, Dickinson CJ, del Valle J, Matsushima M, Todisco A: Cell type-specific requirement of the MAPK pathway for the growth factor action of gastrin. Am J Physiol 1999, 276(6 Pt 1):G1363-72.
• [76]Zimmermann S, Moelling K: Phosphorylation and Regulation of Raf by Akt (Protein Kinase B). Science 1999, 286(5445):1741-4.
• [77]Bierkamp C, Kowalski-Chauvel A, Dehez S, Fourmy D, Pradayrol L, Seva C: Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Oncogene 2002, 21(50):7656-70.
• [78]Mishra P, Senthivinayagam S, Rangasamy V, Sondarva G, Rana B: Mixed Lineage Kinase-3/JNK1 Axis Promotes Migration of Human Gastric Cancer Cells following Gastrin Stimulation. Mol Endocrinol 2010, 24(3):598-607.
• [79]Yu H-G, Nam J-O, Miller NLG, Tanjoni I, Walsh C, Shi L, Kim L, Chen XL, Tomar A, Lim S-T, et al.: p190RhoGEF (Rgnef) Promotes Colon Carcinoma Tumor Progression via Interaction with Focal Adhesion Kinase. Cancer Res 2011, 71(2):360-70.
• [80]Ding J, Yu JP, Li D, Yu HG, Luo HS, Wei WZ: Effect of gastrin on invasiveness of human colon cancer cells. Zhonghua zhong liu za zhi 2005, 27(4):213-5.
• [81]Fjeldbo CS, Bakke I, Erlandsen SE, Holmseth J, Laegreid A, Sandvik AK, Thommesen L, Bruland T: Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats. Am J Physiol Gastrointest Liver Physiol 2012, 302(1):G21-33.
• [82]Ramamoorthy S, Stepan V, Todisco A: Intracellular mechanisms mediating the anti-apoptotic action of gastrin. Biochem Biophys Res Commun 2004, 323(1):44-8.
• [83]Maere S, Heymans K, Kuiper M: BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks. Bioinformatics 2005, 21(16):3448-9.
• [84]Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB: Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 2012, 149(4):780-94.
• [85]Jun Cao J-PY, Chao-Hong L, Lan Z, Hong-Gang Y: Effects of gastrin 17 on β-catenin/Tcf-4 pathway in Colo320WT colon cancer cells. World J Gastroenterol 2006, 12(46):7482-7.
• [86]Clarke PA, Dickson JH, Harris JC, Grabowska A, Watson SA: Gastrin enhances the angiogenic potential of endothelial cells via modulation of heparin-binding epidermal-like growth factor. Cancer Res 2006, 66(7):3504-12.
• [87]Trulsson LM, Gasslander T, Svanvik J: Cholecystokinin-8-induced hypoplasia of the rat pancreas: influence of nitric oxide on cell proliferation and programmed cell death. Basic Clin Pharmacol Toxicol 2004, 95(4):183-90.
• [88]Tiger CF, Krause F, Cedersund G, Palmer R, Klipp E, Hohmann S, Kitano H, Krantz M: A framework for mapping, visualisation and automatic model creation of signal-transduction networks. Mol Syst Biol 2012, 8:578.
• [89]Leach SM, Tipney H, Feng W, Baumgartner WA, Kasliwal P, Schuyler RP, Williams T, Spritz RA, Hunter L: Biomedical discovery acceleration, with applications to craniofacial development. PLoS Comput Biol 2009, 5(3):e1000215.
• [90]Gitter A, Carmi M, Barkai N, Bar-Joseph Z: Linking the signaling cascades and dynamic regulatory networks controlling stress responses. Genome Res 2012, 23(2):365-76.