Cancer drug target identification and node-level analysis of the network of MAPK pathways

  • V. K. MD Aksam
  • V. M. Chandrasekaran
  • Sundaramurthy Pandurangan
Original Article
  • 27 Downloads

Abstract

Mitogen-activated protein kinase (MAPK) pathways extensively studied in cancer and governing intertwined biological process challenges to identify the efficient drug target strategy. Cross-talks among ERK1/2, ERK5, JNK, and p38 amplify signaling flow and lead to the construction of the network of MAPK pathways. A topological analysis reveals that the network exponentially fits the degree distributions and targeting hub proteins causes detrimental to the network. We aim to identify novel drug targets controlling pathological consequences in the signaling flow than killing the cell. Intra-pathway node inhibition causes less perturbation in the network. We set the strategy of considering low degree (< 5) and intra-pathway nodes free from the intertwined regulations as preliminary isolation. Furthermore, nodes with less functionally diverse and significantly contributing to the cancer are isolated using GO annotations. Elements in the network of the MAPK pathways catalogued and analyzed using protein types, subcellular localization, cancerous/non-cancerous nature, target/non-targeted status, and inter- and intra-pathway properties to illustrate their roles in the complex mechanism of cancer. Over a decade of kinases as promising drug targets for cancer, other signal transduction supporting proteins also found to be equally competent. However, kinases interact with various other proteins to gain the higher degree. Similarly, translocation proteins interact with their partners in diverse location to gain the degree and functionally vital. Inhibition of kinases and translocation proteins may draw unexpected side effects. Non-targeted nodes Mos, PAC1, MKP4, 4EBP1, LAD, M3/6, RNPK, and SRF identified as cancer drug targets.

Keywords

Cancer drug target identification Network of MAPK pathways Graph theory Protein types Subcellular localisation 

References

  1. Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147–1157CrossRefGoogle Scholar
  2. Aksam VKMD, Chandrasekaran VM, Pandurangan S (2017) Hub nodes in the network of human mitogen-activated protein kinase (MAPK) pathways: characteristics and potential as drug targets. Inform Med Unlocked 9:173–180CrossRefGoogle Scholar
  3. Albert R, Jeong H, Barabási A-L (2000) Error and attack tolerance of complex networks. Nature 406:378–382CrossRefGoogle Scholar
  4. Amaral LAN, Scala A, Barthelemy M, Stanley HE (2000) Classes of small-world networks. Proc Natl Acad Sci 97:11149–11152CrossRefGoogle Scholar
  5. An O, Pendino V, D’Antonio M, Ratti E, Gentilini M, Ciccarelli FD (2014) NCG 4.0: the network of cancer genes in the era of massive mutational screenings of cancer genomes. Database 2014:bau015CrossRefGoogle Scholar
  6. Antal MA, Bode C, Csermely P (2009) Perturbation waves in proteins and protein networks: applications of percolation and game theories in signaling and drug design. Curr Protein Pept Sci 10:161–172CrossRefGoogle Scholar
  7. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al (2000) Gene Ontology: tool for the unification of biology. Nat Genet 25:25–29CrossRefGoogle Scholar
  8. Barabási A-L, Gulbahce N, Loscalzo J (2010) Network medicine: a network-based approach to human disease. Nat Rev Genet 12:nrg2918Google Scholar
  9. Behar M, Dohlman HG, Elston TC (2007) Kinetic insulation as an effective mechanism for achieving pathway specificity in intracellular signaling networks. Proc Natl Acad Sci 104:16146–16151CrossRefGoogle Scholar
  10. Bhalla US, Iyengar R (1999) Emergent properties of networks of biological signaling pathways. Science (80-) 283:381–387CrossRefGoogle Scholar
  11. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365CrossRefGoogle Scholar
  12. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R et al (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000Google Scholar
  13. Bunnage ME, Gilbert AM, Jones LH, Hett EC (2015) Know your target, know your molecule. Nat Chem Biol 11:368–372CrossRefGoogle Scholar
  14. Butt TR, Karathanasi SK (1995) Transcription factors as drug targets: opportunities for therapeutic selectivity. Gene Expr 4:319–336Google Scholar
  15. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83CrossRefGoogle Scholar
  16. Chen Y-R, Shrivastava A, Tan T-H (2001) Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate. Oncogene 20:367CrossRefGoogle Scholar
  17. Cohen P (2010) Guidelines for the effective use of chemical inhibitors of protein function to understand their roles in cell regulation. Biochem J 425:53–54CrossRefGoogle Scholar
  18. Cornelius SP, Kath WL, Motter AE (2011) Controlling complex networks with compensatory perturbations. arXiv Preprint arXiv:11053726Google Scholar
  19. Csermely P, Korcsmáros T, Kiss HJM, London G, Nussinov R (2013) Structure and dynamics of molecular networks: a novel paradigm of drug discovery: a comprehensive review. Pharmacol Ther 138:333–408CrossRefGoogle Scholar
  20. Darnell JE (2002) Transcription factors as targets for cancer therapy. Nat Rev Cancer 2:740–749CrossRefGoogle Scholar
  21. Dejgaard K, Leffers H, Rasmussen HH, Madsen P, Kruse TA, Gesser B et al (1994) Identification, molecular cloning, expression and chromosome mapping of a family of transformation upregulated hnRNP-K proteins derived by alternative splicing. J Mol Biol 236:33–48CrossRefGoogle Scholar
  22. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290CrossRefGoogle Scholar
  23. Dutkowski J, Kramer M, Surma MA, Balakrishnan R, Cherry JM, Krogan NJ et al (2013) A gene ontology inferred from molecular networks. Nat Biotechnol 31:38–45CrossRefGoogle Scholar
  24. English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23:40–45CrossRefGoogle Scholar
  25. Erenpreisa J, Cragg MS (2010) MOS, aneuploidy and the ploidy cycle of cancer cells. Oncogene 29:5447–5451CrossRefGoogle Scholar
  26. Fliri AF, Loging WT, Volkmann RA (2010) Cause-effect relationships in medicine: a protein network perspective. Trends Pharmacol Sci 31:547–555CrossRefGoogle Scholar
  27. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H et al (2014) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43:D805–D811CrossRefGoogle Scholar
  28. Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A et al (2011) ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res 40:D1100–D1107CrossRefGoogle Scholar
  29. Gibbs JB (2000) Mechanism-based target identification and drug discovery in cancer research. Science (80-) 287:1969–1973CrossRefGoogle Scholar
  30. Gong X, Wu R, Zhang Y, Zhao W, Cheng L, Gu Y et al (2010) Extracting consistent knowledge from highly inconsistent cancer gene data sources. BMC Bioinform 11:76CrossRefGoogle Scholar
  31. Gorgoulis VG, Zacharatos P, Mariatos G, Liloglou T, Kokotas S, Kastrinakis N et al (2001) Deregulated expression of c-mos in non-small cell lung carcinomas: relationship with p53 status, genomic instability, and tumor kinetics. Cancer Res 61:538–549Google Scholar
  32. Gough NR (2011) Focus issue: recruiting players for a game of ERK. Sci Signal 4:9Google Scholar
  33. Grant SK (2009) Therapeutic protein kinase inhibitors. Cell Mol Life Sci 66:1163–1177CrossRefGoogle Scholar
  34. Griffith M, Griffith OL, Coffman AC, Weible JV, McMichael JF, Spies NC et al (2013) DGIdb: mining the druggable genome. Nat Methods 10:1209–1210CrossRefGoogle Scholar
  35. Gschwind A, Fischer OM, Ullrich A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4:361–370CrossRefGoogle Scholar
  36. He R, Yu Z, Zhang R, Zhang Z (2014) Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin 35:1227–1246CrossRefGoogle Scholar
  37. Hopkins AL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4:682–690MathSciNetCrossRefGoogle Scholar
  38. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354CrossRefGoogle Scholar
  39. Imming P, Sinning C, Meyer A (2006) Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 5:821–834CrossRefGoogle Scholar
  40. Inoue A, Sawata SY, Taira K, Wadhwa R (2007) Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis. Proc Natl Acad Sci 104:8983–8988CrossRefGoogle Scholar
  41. Jonsson PF, Bates PA (2006) Global topological features of cancer proteins in the human interactome. Bioinformatics 22:2291–2297CrossRefGoogle Scholar
  42. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132CrossRefGoogle Scholar
  43. Karamouzis MV, Papavassiliou AG (2011) Transcription factor networks as targets for therapeutic intervention of cancer: the breast cancer paradigm. Mol Med 17:1133CrossRefGoogle Scholar
  44. Kitano H (2004a) Opinion: cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer 4:227CrossRefGoogle Scholar
  45. Kitano H (2004b) Biological robustness. Nat Rev Genet 5:826–837CrossRefGoogle Scholar
  46. Kitano H (2007) A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov 6:202CrossRefGoogle Scholar
  47. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A et al (2010) DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res 39:D1035–D1041CrossRefGoogle Scholar
  48. Korcsmáros T, Farkas IJ, Szalay MS, Rovó P, Fazekas D, Spiró Z et al (2010) Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery. Bioinformatics 26:2042–2050CrossRefGoogle Scholar
  49. Levitzki A, Klein S (2010) Signal transduction therapy of cancer. Mol Aspects Med 31:287–329CrossRefGoogle Scholar
  50. Lewis TS, Hunt JB, Aveline LD, Jonscher KR, Louie DF, Yeh JM et al (2000) Identification of novel MAP kinase pathway signaling targets by functional proteomics and mass spectrometry. Mol Cell 6:1343–1354CrossRefGoogle Scholar
  51. Lewitzky M, Simister PC, Feller SM (2012) Beyond ‘furballs’ and ‘dumpling soups’—towards a molecular architecture of signaling complexes and networks. FEBS Lett 586:2740–2750CrossRefGoogle Scholar
  52. Manning AM, Davis RJ (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2:554–565CrossRefGoogle Scholar
  53. McConnell JL, Wadzinski BE (2009) Targeting protein serine/threonine phosphatases for drug development. Mol Pharmacol 75:1249–1261CrossRefGoogle Scholar
  54. Mees C, Nemunaitis J, Senzer N (2009) Transcription factors: their potential as targets for an individualized therapeutic approach to cancer. Cancer Gene Ther 16:103–112CrossRefGoogle Scholar
  55. Muda M, Boschert U, Smith A, Antonsson B, Gillieron C, Chabert C et al (1997) Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J Biol Chem 272:5141–5151CrossRefGoogle Scholar
  56. Nakamura K, Johnson GL (2003) PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem 278:36989–36992CrossRefGoogle Scholar
  57. Nguyen LK, Matallanas D, Croucher DR, von Kriegsheim A, Kholodenko BN (2013) Signalling by protein phosphatases and drug development: a systems-centred view. FEBS J 280:751–765CrossRefGoogle Scholar
  58. Patterson KI, Brummer T, O’brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418:475–489CrossRefGoogle Scholar
  59. Pawson T, Scott JD (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science (80-) 278:2075–2080CrossRefGoogle Scholar
  60. Pearson MA, Fabbro D (2004) Targeting protein kinases in cancer therapy: a success? Expert Rev Anticancer Ther 4:1113–1124CrossRefGoogle Scholar
  61. Plotnikov A, Zehorai E, Procaccia S, Seger R (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta (BBA) Mol Cell Res 1813:1619–1633CrossRefGoogle Scholar
  62. Prasad CK, Mahadevan M, MacNicol MC, MacNicol AM (2008) Mos 3′ UTR regulatory differences underlie species-specific temporal patterns of Mos mRNA cytoplasmic polyadenylation and translational recruitment during oocyte maturation. Mol Reprod Dev 75:1258–1268CrossRefGoogle Scholar
  63. Qin C, Zhang C, Zhu F, Xu F, Chen SY, Zhang P et al (2013) Therapeutic target database update 2014: a resource for targeted therapeutics. Nucleic Acids Res 42:D1118–D1123CrossRefGoogle Scholar
  64. Rask-Andersen M, Almén MS, Schiöth HB (2011) Trends in the exploitation of novel drug targets. Nat Rev Drug Discov 10:579–590CrossRefGoogle Scholar
  65. Roberts PJ, Der CJ (2007) Targeting the Raf–MEK–ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310CrossRefGoogle Scholar
  66. Rohan PJ, Davis P, Moskaluk CA, Kearns M, Krutzsch H, Siebenlist U et al (1993) PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science 259:1763 (YORK THEN WASHINGTON-) CrossRefGoogle Scholar
  67. Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947CrossRefGoogle Scholar
  68. Simpson JC, Pepperkok R (2006) The subcellular localization of the mammalian proteome comes a fraction closer. Genome Biol 7:222CrossRefGoogle Scholar
  69. Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P et al (1999) cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype. Oncogene 18:6063CrossRefGoogle Scholar
  70. Tsukiyama-Kohara K, Vidal SM, Gingras A-C, Glover TW, Hanash SM, Heng H et al (1996) Tissue distribution, genomic structure, and chromosome mapping of mouse and human eukaryotic initiation factor 4E-binding proteins 1 and 2. Genomics 38:353–363CrossRefGoogle Scholar
  71. Wagner EF, Nebreda ÁR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9:537–549CrossRefGoogle Scholar
  72. Ward Y, Gupta S, Jensen P, Wartmann M, Davis RJ, Kelly K (1994) Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature 367:651–654CrossRefGoogle Scholar
  73. Weinberg RA (1996) How cancer arises. Sci Am 275:62–71CrossRefGoogle Scholar
  74. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF et al (2012) Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 92:414–417CrossRefGoogle Scholar
  75. Wiley HS (2014) Open questions: the disrupted circuitry of the cancer cell. BMC Biol 12:88CrossRefGoogle Scholar
  76. Yao Z, Seger R (2009) The ERK signaling cascade—views from different subcellular compartments. Biofactors 35:407–416CrossRefGoogle Scholar
  77. Yee D (2010) Adaptor proteins as targets for cancer prevention. Cancer Prev Res 3:263–265CrossRefGoogle Scholar
  78. Yong H-Y, Koh M-S, Moon A (2009) The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs 18:1893–1905CrossRefGoogle Scholar
  79. Yu Q, Huang J-F (2012) The analysis of the druggable families based on topological features in the protein–protein interaction network. Lett Drug Des Discov 9:426–430CrossRefGoogle Scholar
  80. Zehorai E, Yao Z, Plotnikov A, Seger R (2010) The subcellular localization of MEK and ERK—a novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol Cell Endocrinol 314:213–220CrossRefGoogle Scholar
  81. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–39CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Advanced SciencesVIT UniversityVelloreIndia
  2. 2.PointCross Life Sciences, Inc.BangaloreIndia

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