The nuclear translocation of ERK1/2 as an anticancer target

Nature Communications

Volumn 6, Issue , 2015, Pages

  Plotnikov, Alexander ^a   Flores, Karen ^a   Maik Rachline, Galia ^a   Zehorai, Eldar ^a   Kapri Pardes, Einat ^a   Berti, Denise A ^a   Hanoch, Tamar ^a   Besser, Michal J ^b,c   Seger, Rony ^a  

^a WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^b SHEBA MEDICAL CENTER   (Israel)

^c TEL AVIV UNIVERSITY   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; IMPORTIN 7; KARYOPHERIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MYC PROTEIN; NUCLEAR TRANSLOCATION SIGNAL PHOSPHOMIMETIC PEPTIDE; PROTEIN C FOS; PROTEIN KINASE B; TRANSCRIPTION FACTOR ELK 1; UNCLASSIFIED DRUG; VEMURAFENIB; MAPK1 PROTEIN, HUMAN; PEPTIDE;

APOPTOSIS; CANCER; CYTOPLASM; DRUG; INHIBITION; PEPTIDE; TRANSLOCATION;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; CANCER GROWTH; CANCER INHIBITION; CANCER RECURRENCE; CELL COUNT; CELL FRACTIONATION; CELL PROLIFERATION; CELL STRUCTURE; CELL VIABILITY; CONTROLLED STUDY; CYTOPLASM; EMBRYO; ENZYME INHIBITION; ENZYME NUCLEAR TRANSLOCATION; ENZYME REGULATION; FEMALE; HELA CELL LINE; HUMAN; HUMAN CELL; INTRACELLULAR SIGNALING; MALE; MELANOMA; MELANOMA CELL; MOLECULARLY TARGETED THERAPY; MOUSE; NONHUMAN; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; ACTIVE TRANSPORT; ANIMAL; CANCER TRANSPLANTATION; CELL NUCLEUS; CELL SURVIVAL; CHO CELL LINE; CRICETULUS; DRUG EFFECTS; DRUG SCREENING; FLUORESCENCE MICROSCOPY; HCT116 CELL LINE; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; METABOLISM; NUDE MOUSE; PROTEIN TRANSPORT; SCID MOUSE; TUMOR CELL LINE; TUNEL ASSAY; WESTERN BLOTTING;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BLOTTING, WESTERN; CELL LINE, TUMOR; CELL NUCLEUS; CELL SURVIVAL; CHO CELLS; CRICETULUS; HCT116 CELLS; HELA CELLS; HUMANS; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; IN SITU NICK-END LABELING; MICE, NUDE; MICE, SCID; MICROSCOPY, FLUORESCENCE; MITOGEN-ACTIVATED PROTEIN KINASE 1; MITOGEN-ACTIVATED PROTEIN KINASE 3; MOLECULAR TARGETED THERAPY; NEOPLASM TRANSPLANTATION; PEPTIDES; PROTEIN TRANSPORT; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84926369723     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms7685     Document Type: Article

References (38)

1. Wortzel, I. & Seger, R. The ERK cascade: distinct functions within various subcellular organelles. Genes Cancer 2, 195-209 (2011).
2. Keshet, Y. & Seger, R. The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol. Biol. 661, 3-38 (2010).
3. Morrison, D. K. MAP kinase pathways. Cold Spring Harb. Perspect. Biol. 4, 1-5 (2012).
4. Plotnikov, A., Zehorai, E., Procaccia, S. & Seger, R. The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta 1813, 1619-1633 (2011).
5. Osborne, J. K., Zaganjor, E. & Cobb, M. H. Signal control through Raf: in sickness and in health. Cell Res. 22, 14-22 (2012).
6. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809-819 (2010).
7. Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107-114 (2012).
8. Yap, J. L., Worlikar, S., MacKerell, Jr. A. D., Shapiro, P. & Fletcher, S. Small-molecule inhibitors of the ERK signaling pathway: towards novel anticancer therapeutics. ChemMedChem 6, 38-48 (2011).
9. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207-215 (2012).
10. Callahan, M. K. et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N. Engl. J. Med. 367, 2316-2321 (2012).
11. Solit, D. B. & Rosen, N. Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 364, 772-774 (2011).
12. Mirzoeva, O. K. et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 69, 565-572 (2009).
13. Wee, S. et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69, 4286-4293 (2009).
14. Yao, Z. & Seger, R. The ERK signaling cascade - views from different subcellular compartments. Biofactors 35, 407-416 (2009).
15. Chen, R. H., Sarnecki, C. & Blenis, J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol. Cell. Biol. 12, 915-927 (1992).
16. Chuderland, D. & Seger, R. Protein-protein interactions in the regulation of the extracellular signal-regulated kinase. Mol. Biotechnol. 29, 57-74 (2005).
17. Chuderland, D., Konson, A. & Seger, R. Identification and characterization of a general nuclear translocation signal in signaling proteins. Mol. Cell 31, 850-861 (2008).
18. Plotnikov, A., Chuderland, D., Karamansha, Y., Livnah, O. & Seger, R. Nuclear ERK translocation is mediated by protein kinase CK2 and accelerated by autophosphorylation. Mol. Cell. Biol. 31, 3515-3530 (2011).
19. Flores, K. & Seger, R. Stimulated nuclear import by β-like importins. F1000Prime Rep. 5, doi:10.12703/P12705-12741 (2013).
20. Zehorai, E., Yao, Z., Plotnikov, A. & Seger, R. The subcellular localization of MEK and ERK - a novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol. Cell. Endocrinol. 314, 213-220 (2010).
21. Formstecher, E. et al. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell 1, 239-250 (2001).
22. Casar, B., Pinto, A. & Crespo, P. ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task. Cell Cycle 8, 1007-1013 (2009).
23. Zehorai, E. & Seger, R. Beta-like importins mediate the nuclear translocation of mitogen-activated protein kinases. Mol. Cell. Biol. 34, 259-270 (2014).
24. Gomez-Cabrero, A. et al. Use of transduction proteins to target trabecular meshwork cells: outflow modulation by profilin I. Mol. Vis. 11, 1071-1082 (2005).
25. Nelson, A. R., Borland, L., Allbritton, N. L. & Sims, C. E. Myristoyl-based transport of peptides into living cells. Biochemistry 46, 14771-14781 (2007).
26. Sun, C. et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508, 118-122 (2014).
27. Robarge, K. D. et al. Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479. Bioorg. Med. Chem. Lett. 24, 4714-4723 (2014).
28. Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387-390 (2011).
29. Jiang, C. C. et al. Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS. Cell Death Dis 1, e69 (2010).
30. VanBrocklin, M. W., Verhaegen, M., Soengas, M. S. & Holmen, S. L. Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res. 69, 1985-1994 (2009).
31. Beck, D. et al. Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. Sci. Signal. 6, ra7 (2013).
32. Rapp, U. R., Gotz, R. & Albert, S. BuCy RAFs drive cells into MEK addiction. Cancer Cell 9, 9-12 (2006).
33. Smith, E. R. et al. Nuclear entry of activated MAPK is restricted in primary ovarian and mammary epithelial cells. PLoS ONE 5, e9295 (2010).
34. Lito, P. et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668-682 (2012).
35. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100-103 (2012).
36. Su, F. et al. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 72, 969-978 (2012).
37. Aksamitiene, E. et al. Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells. Cell Signal. 23, 1794-1805 (2011).
38. Zmajkovicova, K. et al. MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. Mol. Cell. 50, 43-55 (2013).