MEK5/ERK5 pathway: The first fifteen years

Biochimica et Biophysica Acta - Reviews on Cancer

Volumn 1825, Issue 1, 2012, Pages 37-48

  Drew, Barbara A ^a   Burow, Matthew E ^a   Beckman, Barbara S ^a  

^a TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Big mitogen activated protein kinase; Cellular signaling; Epithelial to mesenchymal transition; Erk5; Kinase inhibitors; Mitogen activated protein kinase

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; BENXAMIDAZOLE DERIVATIVE; BIX 02188; BIX 02189; CYCLIN DEPENDENT KINASE 5 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE 7; MITOGEN ACTIVATED PROTEIN KINASE 7 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE KINASE 5; MITOGEN ACTIVATED PROTEIN KINASE KINASE 5 INHIBITOR; UNCLASSIFIED DRUG; XMD 8 92;

ANGIOGENESIS; APOPTOSIS; CANCER RESISTANCE; CELL CYCLE; CELL DIFFERENTIATION; CELL GROWTH; CELL SURVIVAL; CONCENTRATION RESPONSE; DRUG TARGETING; ENZYME INHIBITION; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; HUMAN; MALIGNANT TRANSFORMATION; METASTASIS; ONCOGENE; PRIORITY JOURNAL; PROGNOSIS; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION;

CELL DIFFERENTIATION; CELL SURVIVAL; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; MAP KINASE KINASE 5; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASE 7; NEOPLASMS;

EID: 80755148776     PISSN: 0304419X     EISSN: 18792561     Source Type: Journal    
DOI: 10.1016/j.bbcan.2011.10.002     Document Type: Review

References (117)

1. Hayashi M., Fearns C., Eliceiri B., Yang Y., Lee J.D. Big mitogen-activated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis. Cancer Res. Sep 1 2005, 65(17):7699-7706.
2. Roberts O.L., Holmes K., Muller J., Cross D.A., Cross M.J. ERK5 and the regulation of endothelial cell function. Biochem. Soc. Trans. Dec 2009, 37(Pt 6):1254-1259.
3. Wang X., Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell. Signal. Jun 2006, 18(6):753-760.
4. Hayashi M., Kim S.W., Imanaka-Yoshida K., Yoshida T., Abel E.D., Eliceiri B., Yang Y., Ulevitch R.J., Lee J.D. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J. Clin. Invest. Apr 2004, 113(8):1138-1148.
5. Chang L., Karin M. Mammalian MAP kinase signalling cascades. Nature Mar 1 2001, 410(6824):37-40.
6. Avruch J. MAP kinase pathways: the first twenty years. Biochim. Biophys. Acta Aug 2007, 1773(8):1150-1160.
7. Coulombe P., Meloche S. Atypical mitogen-activated protein kinases: structure, regulation and functions. Biochim. Biophys. Acta Aug 2007, 1773(8):1376-1387.
8. Bogoyevitch M.A., Court N.W. Counting on mitogen-activated protein kinases-ERKs 3, 4, 5, 6, 7 and 8. Cell. Signal. Dec 2004, 16(12):1345-1354.
9. Rousseau J., Klinger S., Rachalski A., Turgeon B., Deleris P., Vigneault E., Poirier-Heon J.F., Davoli M.A., Mechawar N., El Mestikawy S., Cermakian N., Meloche S. Targeted inactivation of Mapk4 in mice reveals specific non-redundant functions of Erk3/Erk4 subfamily MAP kinases. Mol. Cell Biol. Dec 2010, 30(24):5752-5763.
10. Mehta P.B., Jenkins B.L., McCarthy L., Thilak L., Robson C.N., Neal D.E., Leung H.Y. MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. Oncogene Mar 6 2003, 22(9):1381-1389.
11. Hsieh F.C., Cheng G., Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem. Biophys. Res. Commun. Sep 23 2005, 335(2):292-299.
12. Montero J.C., Ocana A., Abad M., Ortiz-Ruiz M.J., Pandiella A., Esparis-Ogando A. Expression of Erk5 in early stage breast cancer and association with disease free survival identifies this kinase as a potential therapeutic target. PLoS One 2009, 4(5):e5565.
13. Ostrander J.H., Daniel A.R., Lofgren K., Kleer C.G., Lange C.A. Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells. Cancer Res. May 1 2007, 67(9):4199-4209.
14. Song H., Jin X., Lin J. Stat3 upregulates MEK5 expression in human breast cancer cells. Oncogene Oct 28 2004, 23(50):8301.
15. Mody N., Leitch J., Armstrong C., Dixon J., Cohen P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. Jul 27 2001, 502(1-2):21-24.
16. Ramos-Nino M.E., Blumen S.R., Sabo-Attwood T., Pass H., Carbone M., Testa J.R., Altomare B.A., Mossman B.T. HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. Am. J. Respir. Cell Mol. Feb 2008, 38(2):209-217.
17. Hayashi M., Lee J.D. Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J. Mol. Med. Dec 2004, 82(12):800-808.
18. Kato Y., Tapping R.I., Huang S., Watson M.H., Ulevitch R.J., Lee J.D. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature Oct 15 1998, 395(6703):713.
19. Buschbeck M., Ullrich A. The unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttling. J. Biol. Chem. Jan 28 2005, 280(4):2659-2667.
20. Lee J.D., Ulevitch R.J., Han J. Primary structure of BMK1: a new mammalian map kinase. Biochem. Biophys. Res. Commun. Aug 15 1995, 213(2):715-724.
21. Nishimoto S., Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep. Aug 2006, 7(8):782-786.
22. Zhou G., Bao Z.Q., Dixon J.E. Components of a new human protein kinase signal transduction pathway. J. Biol. Chem. May 26 1995, 270(21):12665.
23. Carvajal-Vergara X., Tabera S., Montero J.C., Esparis-Ogando A., Lopez-Perez R., Mateo G., Gutierrez N., Parmo-Cabanas M., Teixido J., San Miguel J.F., Pandiella A. Multifunctional role of Erk5 in multiple myeloma. Blood Jun 1 2005, 105(11):4492-4499.
24. Zhou C., Nitschke A.M., Xiong W., Zhang Q., Tang Y., Bloch M., Elliott S., Zhu Y., Bazzone L., Yu D., Weldon C.B., Schiff R., McLachlan J.A., Beckman B.S., Wiese T.E., Nephew K.P., Shan B., Burow M.E., Wang G. Proteomic analysis of tumor necrosis factor-alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype. Breast Cancer Res. 2008, 10(6):R105.
25. Weldon C.B., Scandurro A.B., Rolfe K.W., Clayton J.L., Elliott S., Butler N.N., Melnik L.I., Alam J., McLachlan J.A., Jaffe B.M., Beckman B.S., Burow M.E. Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Surgery Aug 2002, 132(2):293-301.
26. Gee J.M., Howell A., Gullick W.J., Benz C.C., Sutherland R.L., Santen R.J., Martin L.A., Ciardiello F., Miller W.R., Dowsett M., Barrett-Lee P., Robertson J.F., Johnston S.R., Jones H.E., Wakeling A.E., Duncan R., Nicholson R.I. Consensus statement. Workshop on therapeutic resistance in breast cancer: impact of growth factor signalling pathways and implications for future treatment. Endocr. Relat. Cancer Jul 2005, 12(Suppl 1):S1-S7.
27. Bild A.H., Yao G., Chang J.T., Wang Q., Potti A., Chasse D., Joshi M.B., Harpole D., Lancaster J.M., Berchuck A., Olson J.A., Marks J.R., Dressman H.K., West M., Nevins J.R. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature Jan 19 2006, 439(7074):353-357.
28. Flaherty P.T., Chopra I., Jain P., Yi S., Allen E., Cavanaugh J. Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway. Bioorg. Med. Chem. Lett. May 1 2010, 20(9):2892-2896.
29. Tanoue T., Nishida E. Molecular recognitions in the MAP kinase cascades. Cell. Signal. May 2003, 15(5):455-462.
30. Widmann C., Gibson S., Jarpe M.B., Johnson G.L. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. Jan 1999, 79(1):143-180.
31. Yang S.H., Sharrocks A.D., Whitmarsh A.J. Transcriptional regulation by the MAP kinase signaling cascades. Gene Nov 27 2003, 320:3-21.
32. Kuida K., Boucher D.M. Functions of MAP kinases: insights from gene-targeting studies. J. Biochem. Jun 2004, 135(6):653-656.
33. Charlson A.T., Zeliadt N.A., Wattenberg E.V. Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin. Toxicol. Appl. Pharmacol. Dec 1 2009, 241(2):143-153.
34. Kamakura S., Moriguchi T., Nishida E. Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J. Biol. Chem. Sep 10 1999, 274(37):26563.
35. Chao T.H., Hayashi M., Tapping R.I., Kato Y., Lee J.D. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J. Biol. Chem. Dec 17 1999, 274(51):36035.
36. English J.M., Vanderbilt C.A., Xu S., Marcus S., Cobb M.H. Isolation of MEK5 and differential expression of alternatively spliced forms. J. Biol. Chem. Dec 1 1995, 270(48):28897.
37. Sun W., Kesavan K., Schaefer B.C., Garrington T.P., Ware M., Johnson N.L., Gelfand E.W., Johnson G.L. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J. Biol. Chem. Feb 16 2001, 276(7):5093.
38. Obara Y., Nakahata N. The signaling pathway leading to extracellular signal-regulated kinase 5 (ERK5) activation via G-proteins and ERK5-dependent neurotrophic effects. Mol. Pharmacol. Jan 2010, 77(1):10-16.
39. Fukuhara S., Marinissen M.J., Chiariello M., Gutkind J.S. Signaling from G protein-coupled receptors to ERK5/Big MAPK 1 involves Galpha q and Galpha 12/13 families of heterotrimeric G proteins. Evidence for the existence of a novel Ras and Rho-independent pathway. J. Biol. Chem. Jul 14 2000, 275(28):21730-21736.
40. Nakaoka Y., Nishida K., Fujio Y., Izumi M., Terai K., Oshima Y., Sugiyama S., Matsuda S., Koyasu S., Yamauchi-Takihara K., Hirano T., Kawase I., Hirota H. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ. Res. Aug 8 2003, 93(3):221-229.
41. Pearson G., English J.M., White M.A., Cobb M.H. ERK5 and ERK2 cooperate to regulate NF-kappaB and cell transformation. J. Biol. Chem. Mar 16 2001, 276(11):7927.
42. Nakamura K., Johnson G.L. PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J. Biol. Chem. Sep 26 2003, 278(39):36989.
43. Seyfried J., Wang X., Kharebava G., Tournier C. A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Mol. Cell Biol. Nov 2005, 25(22):9820.
44. Wang Y., Thakur A., Sun Y., Wu J., Biliran H., Bollig A., Liao D.J. Synergistic effect of cyclin D1 and c-Myc leads to more aggressive and invasive mammary tumors in severe combined immunodeficient mice. Cancer Res. Apr 15 2007, 67(8):3698-3707.
45. Xia Y., Wu Z., Su B., Murray B., Karin M. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. Nov 1 1998, 12(21):3369-3381.
46. Yan C., Luo H., Lee J.D., Abe J., Berk B.C. Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J. Biol. Chem. Apr 6 2001, 276(14):10870.
47. Kondoh K., Terasawa K., Morimoto H., Nishida E. Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Mol. Cell Biol. Mar 2006, 26(5):1679-1690.
48. English J.M., Pearson G., Hockenberry T., Shivakumar L., White M.A., Cobb M.H. Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control. J. Biol. Chem. Oct 29 1999, 274(44):31588.
49. Kato Y., Kravchenko V.V., Tapping R.I., Han J., Ulevitch R.J., Lee J.D. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. Dec 1 1997, 16(23):7054.
50. Terasawa K., Okazaki K., Nishida E. Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes Cells Mar 2003, 8(3):263.
51. Nakamura K., Uhlik M.T., Johnson N.L., Hahn K.M., Johnson G.L. PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. Mol. Cell Biol. Mar 2006, 26(6):2065-2079.
52. Whitmarsh A.J., Davis R.J. Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem. Sci. Dec 1998, 23(12):481-485.
53. Brown M.D., Sacks D.B. Compartmentalised MAPK pathways. Handb. Exp. Pharmacol. 2008, 186:205-235.
54. Brown M.D., Sacks D.B. Protein scaffolds in MAP kinase signalling. Cell. Signal. Apr 2009, 21(4):462-469.
55. McKay M.M., Ritt D.A., Morrison D.K. Signaling dynamics of the KSR1 scaffold complex. Proc. Natl. Acad. Sci. U. S. A. Jul 7 2009, 106(27):11022-11027.
56. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat. Rev. Mol. Cell Biol. Nov 2005, 6(11):827-837.
57. Morrison D.K., Davis R.J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 2003, 19:91-118.
58. Dodge-Kafka K.L., Soughayer J., Pare G.C., Carlisle Michel J.J., Langeberg L.K., Kapiloff M.S., Scott J.D. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature Sep 22 2005, 437(7058):574-578.
59. Nakamura K., Johnson G.L. Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling. Mol. Cell Biol. Jun 2007, 27(12):4566-4577.
60. Tanoue T., Adachi M., Moriguchi T., Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat. Cell Biol. Feb 2000, 2(2):110-116.
61. Suzaki Y., Yoshizumi M., Kagami S., Koyama A.H., Taketani Y., Houchi H., Tsuchiya K., Takeda E., Tamaki T. Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults. J. Biol. Chem. Mar 15 2002, 277(11):9614.
62. Watson F.L., Heerssen H.M., Bhattacharyya A., Klesse L., Lin M.Z., Segal R.A. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat. Neurosci. Oct 2001, 4(10):981-988.
63. Liu L., Cavanaugh J.E., Wang Y., Sakagami H., Mao Z., Xia Z. ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons. Proc. Natl. Acad. Sci. U. S. A. Jul 8 2003, 100(14):8532-8537.
64. Cavanaugh J.E., Ham J., Hetman M., Poser S., Yan C., Xia Z. Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J. Neurosci. Jan 15 2001, 21(2):434.
65. Wang X., Merritt A.J., Seyfried J., Guo C., Papadakis E.S., Finegan K.G., Kayahara M., Dixon J., Boot-Handford R.P., Cartwright E.J., Mayer U., Tournier C. Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol. Cell Biol. Jan 2005, 25(1):336.
66. Nishimoto S., Kusakabe M., Nishida E. Requirement of the MEK5-ERK5 pathway for neural differentiation in Xenopus embryonic development. EMBO Rep. Nov 2005, 6(11):1064.
67. Obara Y., Yamauchi A., Takehara S., Nemoto W., Takahashi M., Stork P.J., Nakahata N. ERK5 activity is required for nerve growth factor-induced neurite outgrowth and stabilization of tyrosine hydroxylase in PC12 cells. J. Biol. Chem. Aug 28 2009, 284(35):23564-23573.
68. Pi X., Garin G., Xie L., Zheng Q., Wei H., Abe J., Yan C., Berk B.C. BMK1/ERK5 is a novel regulator of angiogenesis by destabilizing hypoxia inducible factor 1alpha. Circ. Res. Jun 10 2005, 96(11):1145.
69. Pi X., Yan C., Berk B.C. Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ. Res. Feb 20 2004, 94(3):362.
70. Brunet A., Park J., Tran H., Hu L.S., Hemmings B.A., Greenberg M.E. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell Biol. Feb 2001, 21(3):952-965.
71. Hayashi M., Tapping R.I., Chao T.H., Lo J.F., King C.C., Yang Y., Lee J.D. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J. Biol. Chem. Mar 23 2001, 276(12):8631-8634.
72. Leong M.L., Maiyar A.C., Kim B., O'Keeffe B.A., Firestone G.L. Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J. Biol. Chem. Feb 21 2003, 278(8):5871-5882.
73. Dong F., Gutkind J.S., Larner A.C. Granulocyte colony-stimulating factor induces ERK5 activation, which is differentially regulated by protein-tyrosine kinases and protein kinase C. Regulation of cell proliferation and survival. J. Biol. Chem. Apr 6 2001, 276(14):10811.
74. Buse P., Tran S.H., Luther E., Phu P.T., Aponte G.W., Firestone G.L. Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J. Biol. Chem. Mar 12 1999, 274(11):7253-7263.
75. Mulloy R., Salinas S., Philips A., Hipskind R.A. Activation of cyclin D1 expression by the ERK5 cascade. Oncogene Aug 21 2003, 22(35):5387.
76. Folkman J. Angiogenesis: an organizing principle for drug discovery?. Nat. Rev. Drug Discov. Apr 2007, 6(4):273-286.
77. Holmes D.I., Zachary I.C. Vascular endothelial growth factor regulates stanniocalcin-1 expression via neuropilin-1-dependent regulation of KDR and synergism with fibroblast growth factor-2. Cell. Signal. Mar 2008, 20(3):569-579.
78. Chiariello M., Marinissen M.J., Gutkind J.S. Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol. Cell Biol. Mar 2000, 20(5):1747-1758.
79. Abe J., Takahashi M., Ishida M., Lee J.D., Berk B.C. c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1. J. Biol. Chem. Aug 15 1997, 272(33):20389-20394.
80. Barros J.C., Marshall C.J. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J. Cell Sci. Apr 15 2005, 118(Pt 8):1663.
81. Scapoli L., Ramos-Nino M.E., Martinelli M., Mossman B.T. Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos. Oncogene Jan 22 2004, 23(3):805-813.
82. Schramp M., Ying O., Kim T.Y., Martin G.S. ERK5 promotes Src-induced podosome formation by limiting Rho activation. J. Cell Biol. Jun 30 2008, 181(7):1195-1210.
83. Grunert S., Jechlinger M., Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat. Rev. Mol. Cell Biol. Aug 2003, 4(8):657-665.
84. Kang Y., Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell Aug 6 2004, 118(3):277-279.
85. Yang J., Mani S.A., Donaher J.L., Ramaswamy S., Itzykson R.A., Come C., Savagner P., Gitelman I., Richardson A., Weinberg R.A. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell Jun 25 2004, 117(7):927-939.
86. Arnoux V., Nassour M., L'Helgoualc'h A., Hipskind R.A., Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol. Biol. Cell Nov 2008, 19(11):4738-4749.
87. Parent A.E., Choi C., Caudy K., Gridley T., Kusewitt D.F. The developmental transcription factor slug is widely expressed in tissues of adult mice. J. Histochem. Cytochem. Jul 2004, 52(7):959-965.
88. Nieto M.A. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell Biol. Mar 2002, 3(3):155-166.
89. Thiery J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer Jun 2002, 2(6):442-454.
90. Edme N., Downward J., Thiery J.P., Boyer B. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. J. Cell Sci. Jun 15 2002, 115(Pt 12):2591-2601.
91. Comijn J., Berx G., Vermassen P., Verschueren K., van Grunsven L., Bruyneel E., Mareel M., Huylebroeck D., van Roy F. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell Jun 2001, 7(6):1267-1278.
92. Sosic D., Richardson J.A., Yu K., Ornitz D.M., Olson E.N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell Jan 24 2003, 112(2):169-180.
93. Huber M.A., Azoitei N., Baumann B., Grunert S., Sommer A., Pehamberger H., Kraut N., Beug H., Wirth T. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. Aug 2004, 114(4):569-581.
94. Schwartz S.A., Hernandez A., Mark Evers B. The role of NF-kappaB/IkappaB proteins in cancer: implications for novel treatment strategies. Surg. Oncol. Nov 1999, 8(3):143-153.
95. Weldon C.B., Burow M.E., Rolfe K.W., Clayton J.L., Jaffe B.M., Beckman B.S. NF-kappa B-mediated chemoresistance in breast cancer cells. Surgery Aug 2001, 130(2):143-150.
96. Yamashita S., Miyagi C., Fukada T., Kagara N., Che Y.S., Hirano T. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature May 20 2004, 429(6989):298-302.
97. Fujita N., Jaye D.L., Kajita M., Geigerman C., Moreno C.S., Wade P.A. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell Apr 18 2003, 113(2):207-219.
98. NCBI Homo sapiens [updated updated 14-Jul-2010]; Available from:. http://www.ncbi.nlm.nih.gov/gene/8061.
99. Ramos-Nino M.E., Timblin C.R., Mossman B.T. Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. Cancer Res. Nov 1 2002, 62(21):6065-6069.
100. Hoffmann E., Thiefes A., Buhrow D., Dittrich-Breiholz O., Schneider H., Resch K., Kracht M. MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. J. Biol. Chem. Mar 11 2005, 280(10):9706-9718.
101. Vial E., Sahai E., Marshall C.J. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell Jul 2003, 4(1):67-79.
102. Young M.R., Nair R., Bucheimer N., Tulsian P., Brown N., Chapp C., Hsu T.C., Colburn N.H. Transactivation of Fra-1 and consequent activation of AP-1 occur extracellular signal-regulated kinase dependently. Mol. Cell Biol. Jan 2002, 22(2):587-598.
103. Ramos-Nino M.E., Blumen S.R., Sabo-Attwood T., Pass H., Carbone M., Testa J.R., Altomare D.A., Mossman B.T. HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. Am. J. Respir. Cell Mol. Biol. Feb 2008, 38(2):209-217.
104. Sawhney R.S., Liu W., Brattain M.G. A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. J. Cell. Physiol. Apr 2009, 219(1):152-161.
105. Parsons J.T., Slack-Davis J., Tilghman R., Roberts W.G. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res. Feb 1 2008, 14(3):627-632.
106. Sticht C., Freier K., Knopfle K., Flechtenmacher C., Pungs S., Hofele C.M., Hahn M., Joos S., Lichter P. Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC). Neoplasia May 2008, 10(5):462-U26.
107. Esparis-Ogando A., Diaz-Rodriguez E., Montero J.C., Yuste L., Crespo P., Pandiella A. Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. Mol. Cell Biol. Jan 2002, 22(1):270-285.
108. Weldon C.B., Parker A.P., Patten D., Elliott S., Tang Y., Frigo D.E., Dugan C.M., Coakley E.L., Butler N.N., Clayton J.L., Alam J., Curiel T.J., Beckman B.S., Jaffe B.M., Burow M.E. Sensitization of apoptotically-resistant breast carcinoma cells to TNF and TRAIL by inhibition of p38 mitogen-activated protein kinase signaling. Int. J. Oncol. Jun 2004, 24(6):1473-1480.
109. NCBI Entrez Gene. National Institute of Health [updated September 1, 2010]; Available from:. http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene.
110. Takahashi N., Saito Y., Kuwahara K., Harada M., Tanimoto K., Nakagawa Y., Kawakami R., Nakanishi M., Yasuno S., Usami S., Yoshimura A., Nakao K. Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. J. Mol. Cell. Cardiol. Jan 2005, 38(1):185-192.
111. Flaherty P.T., Chopra I., Jain P., Yi S.Y., Allen E., Cavanaugh J. Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway. Bioorg. Med. Chem. Lett. May 1 2010, 20(9):2892-2896.
112. Yang Q., Deng X., Lu B., Cameron M., Fearns C., Patricelli M.P., Yates J.R., Gray N.S., Lee J.D. Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell Sep 14 2010, 18(3):258-267.
113. Bernardi R., Pandolfi P.P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat. Rev. Mol. Cell Biol. Dec 2007, 8(12):1006-1016.
114. Salomoni P., Pandolfi P.P. The role of PML in tumor suppression. Cell Jan 25 2002, 108(2):165-170.
115. Normanno N., De Luca A., Maiello M.R., Campiglio M., Napolitano M., Mancino M., Carotenuto A., Viglietto G., Menard S. The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J. Cell. Physiol. May 2006, 207(2):420-427.
116. O'Grady M., Raha D., Hanson B.J., Bunting M., Hanson G.T. Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer. BMC Cancer Oct 3 2005, 5.
117. Tatake R.J., O'Neill M.M., Kennedy C.A., Wayne A.L., Jakes S., Wu D., Kugler S.Z., Kashem M.A., Kaplita P., Snow R.J. Identification of pharmacological inhibitors of the MEK5/ERK5 pathway. Biochem. Biophys. Res. Commun. Dec 5 2008, 377(1):120-125.