MAPK SIGNALLING PATHWAY: ROLE IN CANCER PATHOGENESIS
Cancer is one of the prime causes of death presently. In normal cells, the firmly regulated pathway relays extracellular signals from the cell membrane to nucleus through a cascade of phosphorylation events. The Mitogen-Activated Protein Kinase (MAPK) cascades are among the most thoroughly studied signal transduction systems and have been proven to participate in a diverse array of cellular programs consisting of cell differentiation, cell movement, cell division and cell death. Constitutive activation of the MAPK cascade is associated with the carcinogenesis and melanoma development because of activating mutations within the B-RAF and RAS genes or other genetic or epigenetic modifications in their components or upstream activation of cell-surface receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g. BCR-ABL) leading to elevated signaling activity eliciting cellular proliferation, invasion, metastasis, migration, survival and angiogenesis. Even in the absence of apparent genetic mutations, MAPK pathway has been stated to be activated in over 50% of Acute Myelogenous Leukemia (AML) and acute lymphocytic leukemia. In this brief review, we are about to outline the current advances in understanding the regulation of Mitogen-activated protein kinase signaling system and how can we generate specificity.
2. James A. McCubrey, Linda S. Steelman, Steven L. Abrams, John T. Lee, Fumin Chang, Fred E. Bertrand, et.al: Roles of the RAF/MEK/ERK and PI3K/PTEN/ AKT pathways in malignant transformation and drug resistance. Advances in enzyme regulation 2006;46:249-79.
3. Leslie A. Fecher, Ravi K. Amaravadi and Keith T. Flaherty: The MAPK pathway in melanoma. Current opinion in oncology 2008;20:183–89.
4. Antonella De Luca, Monica R Maiello, Amelia D’Alessio, Maria Pergameno & Nicola Normanno: The RAS/RAF/MEK/ERK and the PI3K/AKT ignaling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert opinion on therapeutic target 2012;16(Suppl.2):S17-27.
5. Richard Treisman: Regulation of transcription by MAP Kinase cascades. Current opinion in cell biology 1996;8:205-15.
6. Hans J. Schaeffer,Michael J. Weber: Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers. Moll Cell Biol 1999;19:2435-44.
7. Gajanan S. Inamdar, SubbaRao V. Madhunapantula, Gavin P. Robertson: Targeting the MAPK pathway in melanoma: Why some approaches succeed and other fail. Biochem Pharmacol 2010;80:624-37.
8. Dhomen N, Marais R: BRAF signaling and targeted therapies in melanoma. ?Hematol Oncol Clin North Am 2009;23:529–45.
9. Lopez-Bergami P, Fitchman B, Ronai Z: Understanding signaling cascades in melanoma. Photochem Photobiol 2008;84:289–306.
10. Giehl K: Oncogenic ras in tumour progression and metastasis. Biol Chem 2005;386:193–205.
11. Shaw RJ, Cantley LC: Ras, PI(3)K and mTOR ignaling controls tumour cell growth. Nature 2006;441:424-30.
12. Gureasko J, Galush WJ, Boykevisch S, Sondermann H, Bar-Sagi D, Groves JT, Kuriyan J (2008) Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol 15(5):452–61.
13. Lavoie H, Therrien M: Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 2015;16:281-98.
14. Mercer KE, Pritchard CA: Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 2003;1653:25–40.
15. Downward J: Targeting RAS ignaling pathways in cancer therapy. Nat Rev Cancer 2003;3:11-22.
16. Yoon S, Seger R (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24(1):21–44.
17. Wu X., S. J. Noh, G. Zhou, J. E. Dixon, K. L Guan: Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor stimulated Hela cells. J. Biol. Chem 1996;271:3265–71.
18. Hagemann C, Rapp Ulf R: Isotype- specific functions of RAF kinases. Exp Cell Res 1999;253:34-46.
19. Khanam U, Malik BK, Mathur P, Rathi B: Identification for novel inhibitors for Mitogen Activated Protein Kinase Kinase 4 by virtual screening and molecular dynamics simulation techniques. Int J Pharm Pharm Sci 2016;8:262-68.
20. Kaladhar B. Reddy, Joseph S. Krueger, Sudhir B. Kondapaka, Clement A. Diglio: Mitogen activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. Int J cancer 1999;82:268-73.
21. Canagarajah, B. J, A. Khokhlatchev, M. H. Cobb, E. J. Goldsmith: Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 1997;90:859–69.
22. Payne D.M, Rossomando A.J, Martino P, Erickson A.K, Her J H, Shabanowitz J, et.al: Identification of regulatory Phosphorylation sites in pp42/Mitogen Activated Protein Kinases (MAP Kinases). EMBO J 1991;10:885-92.
23. Kortylewski M, Heinrich PC, Kauffmann ME, Bohm M, Mackiewicz A, Behrmann I: Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. Biochem J 2001;357:297–303.
24. Widlund HR, Fisher DE: Microphthalamia-associated transcription factor: A critical regulator of pigment cell development and survival. Oncogene 2003;22:3035–41.
25. Smalley KS: A pivotal role for ERK in the oncogenic behavior of malignant melanoma, Int J Cancer 2003;104:527–32.
26. Giuliani N, Lunghi P, Morandi F, Colla S, Bonomini S, Hojden M, et.al: Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma- induced angiogenesis. Leukemia 2004;18:628–35.
27. Marcia S. Brose, Patricia Volpe, Michael Feldman, Madhu Kumar, Irum Rishi, Renee Gerrero, et.al: BRAF and RAS Mutations in Human Lung Cancer and Melanoma. Cancer Res 2002;62(23):6997-7000.
28. Madhunapantula SV, Robertson GP: Is B-Raf a good therapeutic target for melanoma and other malignancies? Cancer Res 2008;68:5–8.
29. Gollob JA, Wilhelm S, Carter C, Kelley SL: Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006;33:392–406.
30. Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL, et al. :Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003;17:1263–93.
31. Ponti C, Gibellini D, Boin F, Melloni E, Manzoli FA, Cocco L, et al.: Role of CREB transcription factor in c-fos activation in natural killer cells. Eur J Immunol 2002;32:3358–65.
32. Adachi T, Kar S, Wang M, Carr BI: Transient and sustained ERK phosphorylation and nuclear translocation in growth control. J Cell Physiol 2002;192:151–59.
33. Tresini M, Lorenzini A, Frisoni L, Allen RG, Cristofalo VJ: Lack of Elk-1 phosphorylation and dysregulation of the extracellular regulated kinase signaling pathway in senescent human fibroblast. Exp Cell Res 2001;269:287-300.
34. Deng X, Kornblau SM, Ruvolo PP, May Jr. WS: Regulation of Bcl2 phosphorylation and potential significance for leukemic cell chemoresistance. J Natl Cancer Inst Monogr 2001;28:30–37.
35. Carter BZ, Milella M, Tsao T, McQueen T, Schober WD, Hu W, et al.: Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia. Leukemia 2003;17:2081–89.
36. Gelinas C, White E: BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev 2006;19:1263–68.
37. Steelman LS, Bertrand FE, McCubrey JA: The complexity of PTEN: mutation, marker and potential target for therapeutic intervention. Expert Opin Therap Targets 2004:8537–50.
38. Campbell PM, Der CJ: Oncogenic ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol 2004;14:105–114.
39. Curtin JA, Busam K, Pinkel D, Bastian BC: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24:4340–46.
40. Panka DJ, Atkins MB, Mier JW: Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin Cancer Res 2006;12:2371s–75s.
41. Cruz J, Reis-Filho JS, Silva P, Lopes JM: Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas. Oncology 2003;65:72–82.
42. Recio JA, Merlino G: Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2, and cyclin D1. Oncogene 2002;21:1000–08.
43. Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P: Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 1996;15:5314–25.
44. Keller ET, Fu Z, Brennan M: The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein. J Cell Biochem 2005;94:273–78.
45. Katz M, Amit I, Yarden Y: Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta 2007;1773:1161-76.
46. Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, et al: Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 2003;95:1878–90.
47. Markandeyan D, Santhaligam K, Kannaiyan S, Sanmathi S, Benedict P: Virtual screening of phytochemicals of Morinda citrifolia as anti inflammatory and anti Alzheimer agents using Molegro virtual docker on p38? Mitogen Activated Protein Kinase enzyme. Asian J Pharm Clin Res 2015;8:141-45.
48. Normanno M, De Luca A, Mailello MR, Campiglio M, Napolitano M, Mancino M, et al: The MEK/MAPK Pathway Is Involved in the Resistance of Breast Cancer Cells to the EGFR Tyrosine Kinase Inhibitor Gefitinib. Cellular Physiology 2006;207:420-27.
49. Normanno N, Tejpar S, Morgillo F, De Luca A, Van cutsem E, Ciardiello F: Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 2009;6:519-27.
50. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL, et al: FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001;97:3589–95.
51. Wellbrock C, Karasarides M, Marais R: The RAF proteins take centre stage—review. Nat Rev Mol Cell Biol 2004;5:875–85.
52. Zebisch A, Staber PB, Delavar A, Bodner C, Hiden K, Fischereder K, et al: Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res 2006;66:3401–08.
53. Wong CW, Fan YS, Chan TL, Chan A S W, Ho L C, Ma T K F, et al: BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol 2005;58:640– 44.
54. Bauer J, Curtin JA, Pinkel D, Bastian BC: Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127:179–182.
55. Cory M. Johannessen, Jesse S. Boehm, So Young Kim, Sapana R. Thomas, Leslie Wardwell, Laura A. Johnson, et.al: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468:968-72.
56. Johnson L. N., Lowe E. D., Noble M. E., Owen D. J: The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett. 1998;430:1–11.
57. Schubbert S, Shannon K, Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308.
58. Wan PT, Garnett MJ, Roe SM, Lee S, jones M, Marshal C J, et al: Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004;116:855–67.
59. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al: Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
60. Pollock PM, Harper UL, Hansen KS, Stark M, Robbins CM, Moses TY, et.al: High frequency of BRAF mutations in nevi. Nat Genet 2003;33:19–20.
61. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–47.
62. Lake D., Corrêa S.A.L, MüllerJ: Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol Life Sci 2016;73:4397-4413.
63. Burotto M MD, Chiou V.L MD, Lee J, Kohn E.C MD: The MAPK pathway across different Malignancies: A new perspective. Cancer 2014;120:3446-56.
64. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al: BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003;88:5399–5404.
65. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforova YE, Fagin JA: High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC- RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454–57.
66. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B,et al: BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003;95:25–627.
67. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418:934.
68. Yuen ST, Davies H, Chan TL, HO JW, Bignell GR, Cox C, et al: Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002;62:6451–55.
69. Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Hauss J, et al: Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52:706-12.
70. Sommerer F, Vieth M, Markwarth A, May A, Stole M, Vomschloss S, et al: Mutations of BRAF and KRAS2 in the development of Barrett’s adenocarcinoma. Oncogene 2004;23:554–58.
71. Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Lee JH, et al: BRAF and KRAS mutations in stomach cancer. Oncogene 2003;22:6942–45.
72. Weber A, Langhanki L, Sommerer F, Markwarth A, Wittekind C, Tannapfel A, et al: Mutations of the BRAF gene in squamous cell carcinoma of the head and neck. Oncogene 2003;22:4757–59.
73. Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M: Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 2002;62:7001–03.
74. Singer G, Oldt R 3rd, Cohen Y, Wang BS, Sidransky D, Kurman RJ, et al: Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003;95:484–86.
75. Lee JW, Soung YH, Park WS, Kim SY, Nam SW, Min WS, et al: BRAF mutations in acute leukemias. Leukemia 2004;18:170–72.
76. Kumar SM, Yu H, Edwards R, Chem L, Kazianis S, Herlyn M: et al: Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma. Cancer Res 2007;67:3177–84.
77. M.J.Garnett, R. Marais: Guilty as charged: B-Raf is a human oncogene, Cancer Cell 2004;6:313–19.
78. Guan K.L, Figueroa C., Brtva T. R, Zhu T, Taylor J, Barber T.D, Vojtek A.B: Negative regulation of the serine/threonine kinase B-Raf by Akt. J. Biol. Chem.,2001;275:27354–59.
79. Georgia Hatzivassiliou, Kyung Song, Ivana Yen, Barbara J. Brandhuber, Daniel J. Anderson, Ryan Alvarado, et al: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010;464:43-35.
80. Murugan AK, Dong J, Xie J, Xing M: MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas. Cell Cycle 2009;8:2122-24.
81. Pao W, Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-74.
82. Kumar S, Purohit P, Dagar S: A review: Status of genetic modulated Nonsmall cell lung cancer targets and treatments(current updates in drugs for nonsmall cell lung cancer treatment. Asian J Pharm Clin Res 2018;11:40-55.
83. Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, et al: Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003;63:756–59.
84. Christiansen DH, Andersen MK, Desta F, Pedersen-Bjergaard J: Mutations of genes in the receptor tyrosine kinase (RTK) RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2005;19:2232–40.
85. Keiran S.M. Smalley, Mercedes Lioni,?Maurizia Dalla Palma, Min Xiao, Brijal Desai, Suzanne Egyhazi, et.al: Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas. Mol Cancer Ther 2008;7(9):2876-83.
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