Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Acta Pharmacologica Sinica

Volumn 37, Issue 3, 2016, Pages 285-294

  Liu, Rui ^a   Proud, Christopher G ^a  

^a SOUTH AUSTRALIAN HEALTH AND MEDICAL RESEARCH INSTITUTE   (Australia)

Author keywords

Alzheimer's disease; atherosclerosis; cancer; cardiovascular disease; depression; eEF2K; hypertension; mRNA translation; neurodegenerative disease; kinase

Indexed keywords

ELONGATION FACTOR 2 KINASE; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN KINASE INHIBITOR;

ATHEROSCLEROSIS; ATHEROSCLEROTIC PLAQUE; CANCER CELL; CANCER GROWTH; CANCER SURVIVAL; CARCINOGENESIS; CARDIOVASCULAR DISEASE; DEGENERATIVE DISEASE; DEPRESSION; HUMAN; NEOPLASM; NERVE CELL; NERVE CELL PLASTICITY; NONHUMAN; PROTEIN CONFORMATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; PULMONARY HYPERTENSION; REVIEW; SOLID TUMOR; ANIMAL; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; CHEMISTRY; DRUG DEVELOPMENT; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; NEURODEGENERATIVE DISEASES;

ANIMALS; CARDIOVASCULAR DISEASES; DRUG DISCOVERY; ELONGATION FACTOR 2 KINASE; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; NEURODEGENERATIVE DISEASES; PROTEIN KINASE INHIBITORS;

EID: 84959520989     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2015.123     Document Type: Review

References (66)

1. Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, et al. Global quantification of mammalian gene expression control. Nature 2011; 473: 337-42.
2. Kenney JW, Moore CE, Wang X, Proud CG. Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles. Adv Biol Regul 2014; 55: 15-27.
3. Carlberg U, Nilsson A, Nygard O. Functional properties of phos-phorylated elongation factor 2. Eur J Biochem 1990; 191: 639-45.
4. Ryazanov AG, Pavur KS, Dorovkov MV. Alpha kinases: a new class of protein kinases with a novel catalytic domain. Curr Biol 1999; 9: R43-5.
5. Middelbeek J, Clark K, Venselaar H, Huynen MA, van Leeuwen FN. The alpha-kinase family: an exceptional branch on the protein kinase tree. Cell Mol Life Sci 2010; 67: 875-90.
6. Yamaguchi H, Matsushita M, Nairn AC, Kuriyan J. Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 2001; 7: 1047-57.
7. Ye Q, Crawley SW, Yang Y, Cote GP, Jia Z. Crystal structure of the alpha-kinase domain of Dictyostelium myosin heavy chain kinase A. Sci Signal 2010; 3: ra17.
8. Drennan D, Ryazanov AG. Alpha-kinases: analysis of the family and comparison with conventional protein kinases. Prog Biophys Mol Biol 2004; 85: 1-32.
9. Pyr Dit Ruys S, Wang X, Smith EM, Herinckx G, Hussain N, Rider MH, et al. Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase. Biochem J 2012; 442: 681-92.
10. Tavares CD, O'Brien JP, Abramczyk O, Devkota AK, Shores KS, Ferguson SB, et al. Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence. Biochemistry 2012; 51: 2232-45.
11. Crawley SW, Gharaei MS, Ye Q, Yang Y, Raveh B, London N, et al. Autophosphorylation activates Dictyostelium myosin II heavy chain kinase A by providing a ligand for an allosteric binding site in the alpha-kinase domain. J Biol Chem 2011; 286: 2607-16.
12. Wang X, Regufe da MS, Liu R, Moore CE, Xie J, Lanucara F, et al. Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling. Mol Cell Biol 2014; 34: 4088-103.
13. Moore CE, Regufe da MS, Mikolajek H, Proud CG. A conserved loop in the catalytic domain of eukaryotic elongation factor 2 kinase plays a key role in its substrate specificity. Mol Cell Biol 2014; 34: 2294-307.
14. Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, et al. The molecular mechanism of eukaryotic elongation factor 2 kinase activation. J Biol Chem 2014; 289: 23901-16.
15. Kruiswijk F, Yuniati L, Magliozzi R, Low TY, Lim R, Bolder R, et al. Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress. Sci Signal 2012; 5: ra40.
16. Wang X, Xie J, da Mota SR, Moore CE, Proud CG. Regulated stability of eukaryotic elongation factor 2 kinase requires intrinsic but not ongoing activity. Biochem J 2015; 467: 321-31.
17. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J 2001; 20: 4370-9.
18. Browne GJ, Proud CG. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004; 24: 2986-97.
19. Browne GJ, Proud CG. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004; 24: 2986-97.
20. Connolly E, Braunstein S, Formenti S, Schneider RJ. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol 2006; 26: 3955-65.
21. Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, et al. AMP-activated protein kinase protects cardiomyocytes against hypoxic Injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 2005; 25: 9554-75.
22. Moore CE, Mikolajek H, Regufe da MS, Wang X, Kenney JW, Werner JM, et al. Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia. Mol Cell Biol 2015; 35: 1788-804.
23. Dorovkov MV, Pavur KS, Petrov AN, Ryazanov AG. Regulation of elongation factor-2 kinase by pH. Biochemistry 2002; 41: 13444-50.
24. Hardie DG. AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr 2014; 34: 31-55.
25. Iadevaia V, Liu R, Proud CG. mTORC1 signaling controls multiple steps in ribosome biogenesis. Semin Cell Dev Biol 2014; 36: 113-20.
26. Proud CG. Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J 2007; 403: 217-34.
27. Horman S, Browne GJ, Krause U, Patel JV, Vertommen D, Bertrand L, et al. Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr Biol 2002; 12: 1419-23.
28. Browne GJ, Finn SG, Proud CG. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J Biol Chem 2004; 279: 12220-31.
29. Gschwendt M, Kittstein W, Marks F. Elongation factor-2 kinase: effective inhibition by the novel protein kinase inhibitor rottlerin and relative insensitivity towards staurosporine. FEBS Lett 1994; 338: 85-8.
30. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351: 95-105.
31. Arora S, Yang JM, Kinzy TG, Utsumi R, Okamoto T, Kitayama T, et al. Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res 2003; 63: 6894-9.
32. Chen Z, Gopalakrishnan SM, Bui MH, Soni NB, Warrior U, Johnson EF, et al. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. J Biol Chem 2011; 286: 43951-8.
33. Devkota AK, Tavares CD, Warthaka M, Abramczyk O, Marshall KD, Kaoud TS, et al. Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact. Biochemistry 2012; 51: 2100-12.
34. Devkota AK, Warthaka M, Edupuganti R, Tavares CD, Johnson WH, Ozpolat B, et al. High-throughput screens for eEF-2 kinase. J Biomol Screen 2013; 19: 445-52.
35. Edupuganti R, Wang Q, Tavares CD, Chitjian CA, Bachman JL, Ren P, et al. Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors. Bioorg Med Chem 2014; 22: 4910-6.
36. Cho SI, Koketsu M, Ishihara H, Matsushita M, Nairn AC, Fukazawa H, et al. Novel compounds, '1,3-selenazine derivatives' as specific inhibitors of eukaryotic elongation factor-2 kinase. Biochim Biophys Acta 2000; 1475: 207-15.
37. Lockman JW, Reeder MD, Suzuki K, Ostanin K, Hoff R, Bhoite L, et al. Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues. Bioorg Med Chem Lett 2010; 20: 2283-6.
38. Hori H, Nagasawa H, Ishibashi M, Uto Y, Hirata A, Saijo K, et al. TX-1123: an antitumor 2-hydroxyarylidene-4-cyclopentene-1,3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity. Bioorg Med Chem 2002; 10: 3257-65.
39. Wang Q, Edupuganti R, Tavares CD, Dalby KN, Ren P. Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis. Front Mol Biosci 2015; 2: 9.
40. Leprivier G, Sorensen PH. How does oncogene transformation render tumor cells hypersensitive to nutrient deprivation? Bioessays 2014; 36: 1082-90.
41. Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, et al. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS One 2012; 7: e41171.
42. Liu JC, Voisin V, Wang S, Wang DY, Jones RA, Datti A, et al. Combined deletion of PTEN and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K. EMBO Mol Med 2014; 6: 1542-60.
43. Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 2014; 517: 497-500.
44. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 2013; 153: 1064-79.
45. Xie CM, Liu XY, Sham KW, Lai JM, Cheng CH. Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells. Autophagy 2014; 10: 1495-508.
46. Py BF, Boyce M, Yuan J. A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses. Autophagy 2009; 5: 393-6.
47. Price DJ, Nemenoff RA, Avruch J. Purification of a hepatic S6 kinase from cycloheximide-treated rats. J Biol Chem 1989; 264: 13833.
48. Beugnet A, Tee AR, Taylor PM, Proud CG. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J 2003; 372: 555-66.
49. Wang N, Feng Y, Tan HY, Cheung F, Hong M, Lao L, et al. Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma. J Ethnopharmacol 2015; 164: 309-18.
50. Hundal RS, Salh BS, Schrader JW, Gomez-Munoz A, Duronio V, Steinbrecher UP. Oxidized low density lipoprotein inhibits macrophage apoptosis through activation of the PI 3-kinase/PKB pathway. J Lipid Res 2001; 42: 1483-91.
51. Chen JH, Riazy M, Smith EM, Proud CG, Steinbrecher UP, Duronio V. Oxidized LDL-mediated macrophage survival involves elongation factor-2 kinase. Arterioscler Thromb Vasc Biol 2009; 29: 92-8.
52. Zhang P, Riazy M, Gold M, Tsai SH, McNagny K, Proud C, et al. Impairing eukaryotic elongation factor 2 kinase activity decreases atherosclerotic plaque formation. Can J Cardiol 2014; 30: 1684-8.
53. Usui T, Nijima R, Sakatsume T, Otani K, Kameshima S, Okada M, et al. Eukaryotic elongation factor 2 kinase controls proliferation and migration of vascular smooth muscle cells. Acta Physiol (Oxf) 2015; 213: 472-80.
54. Usui T, Okada M, Hara Y, Yamawaki H. Exploring calmodulin-related proteins, which mediate development of hypertension, in vascular tissues of spontaneous hypertensive rats. Biochem Biophys Res Commun 2011; 405: 47-51.
55. Usui T, Okada M, Hara Y, Yamawaki H. Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation. Am J Physiol Heart Circ Physiol 2013; 305: H756-68.
56. Kameshima S, Kazama K, Okada M, Yamawaki H. Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling. Am J Physiol Heart Circ Physiol 2015; 308: H1298-305.
57. Richter JD, Klann E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Develop 2009; 23: 1-11.
58. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron 2009; 61: 10-26.
59. Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 2008; 59: 70-83.
60. Gildish I, Manor D, David O, Sharma V, Williams D, Agarwala U, et al. Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice. Learn Mem 2012; 19: 116-25.
61. Walden WE, Thach RE. Translational control of gene expression in a normal fibroblast. Characterization of a subclass of mRNAs with unusual kinetic properties. Biochemistry 1986; 25: 2033-41.
62. Kenney JW, Sorokina O, Genheden M, Sorokin A, Armstrong JD, Proud CG. Dynamics of elongation factor 2 kinase regulation in cortical neurons in response to synaptic activity. J Neurosci 2015; 35: 3034-47.
63. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91-5.
64. Nosyreva E, Kavalali ET. Activity-dependent augmentation of spontaneous neurotransmission during endoplasmic reticulum stress. J Neurosci 2010; 30: 7358-68.
65. Heise C, Gardoni F, Culotta L, Di LM, Verpelli C, Sala C. Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. Front Cell Neurosci 2014; 8: 35.
66. Ma T, Chen Y, Vingtdeux V, Zhao H, Viollet B, Marambaud P, et al. Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid beta. J Neurosci 2014; 34: 12230-8.