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ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation

Abstract

Heterogeneous nuclear ribonucleoprotein K (hnRNP-K) is one of a family of 20 proteins that are involved in transcription and post-transcriptional messenger RNA metabolism. The mechanisms that underlie regulation of hnRNP-K activities remain largely unknown. Here we show that cytoplasmic accumulation of hnRNP-K is phosphorylation-dependent. Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Serum stimulation or constitutive activation of ERK kinase (MEK1) results in phosphorylation and cytoplasmic accumulation of hnRNP-K. Mutation at ERK phosphoacceptor sites in hnRNP-K abolishes the ability to accumulate in the cytoplasm and renders the protein incapable of regulating translation of mRNAs that have a differentiation-control element (DICE) in the 3′ untranslated region (UTR). Similarly, treatment with a pharmacological inhibitor of the ERK pathway abolishes cytoplasmic accumulation of hnRNP-K and attenuates inhibition of mRNA translation. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation.

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Figure 1: In vivo phosphorylation of HA–hnRNP-K by ERK is required for translational inhibition of Luc–2R.
Figure 2: Association of LOX mRNA with K protein and inhibition of its translation in vitro is not phosphorylation-dependent.
Figure 3: Cytoplasmic accumulation of hnRNP-K upon ERK phosphorylation and serum stimulation.
Figure 4: Cytoplasmic accumulation of ERK-phosphorylated endogenous hnRNP-K upon serum stimulation.

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References

  1. Weighardt, F., Biamonti, G. & Riva, S. Bioessays 18, 747–756 (1996).

    Article  CAS  Google Scholar 

  2. Krecic, A. & Swanson, M. Curr. Opin. Cell Biol. 11, 363–371 (1999).

    Article  CAS  Google Scholar 

  3. Nakielny, S. & Dreyfuss, G. Cell 99, 677–690 (1999).

    Article  CAS  Google Scholar 

  4. Bomsztyk, K., Seuningen, I., Suzuki, H., Denisenko, O. & Ostrowski, J. FEBS Lett. 403, 113–115 (1997).

    Article  CAS  Google Scholar 

  5. Hobert, O., Jallal, B., Schlessinger, J. & Ullrich, A. J. Biol. Chem. 269, 20225–20228 (1994).

    CAS  PubMed  Google Scholar 

  6. Michael, W., Eder, P. & Dreyfuss, G. EMBO J. 16, 3587–3598 (1997).

    Article  CAS  Google Scholar 

  7. Lee, M-H., Mori, S. & Raychaudhuri, P. J. Biol. Chem. 271, 3420–3427 (1996).

    Article  CAS  Google Scholar 

  8. Du, Q., Melnikova, I. & Gardner, P. J. Biol. Chem. 273, 19877–19888 (1998).

    Article  CAS  Google Scholar 

  9. Miau, L-H., Chang, C-J., Shen, B-J., Tsai, W-H. & Lee, S-C. J. Biol. Chem. 273, 10784–10791 (1998).

    Article  CAS  Google Scholar 

  10. Tomonaga, T. & Levens, D. J. Biol. Chem. 270, 4875–4881 (1995).

    Article  CAS  Google Scholar 

  11. Hovemann, B., Reim, I., Werner, S., Katz, S. & Saumweber, H. Gene 245, 127–137 (2000).

    Article  CAS  Google Scholar 

  12. Tomonaga, T. & Levens, D. Proc. Natl Acad. Sci. USA 93, 5830–5835 (1996).

    Article  CAS  Google Scholar 

  13. Ostareck-Lederer, A., Ostareck, D., Standart, N. & Thiele, B. EMBO J. 13, 1476–1481 (1994).

    Article  CAS  Google Scholar 

  14. Ostareck, D. et al. Cell 89, 597–606 (1997).

    Article  CAS  Google Scholar 

  15. Thiele, B. et al. Nucleic Acids Res. 27, 1828–18 (1999).

    Article  CAS  Google Scholar 

  16. Collier, B., Goobar-Larsson, L., Sokolowski, M. & Schwartz, S. J. Biol. Chem. 273, 22648–22656 (1998).

    Article  CAS  Google Scholar 

  17. Bstelo, X., Suen, K-L., Michael, W., Dreyfuss, G. & Barbacid, M. Mol. Cell. Biol. 15, 1324–1332 (1995).

    Article  Google Scholar 

  18. Taylor, S. & Shalloway, D. Nature 368, 867–874 (1994).

    Article  CAS  Google Scholar 

  19. Weng Z. et al. Mol. Cell. Biol. 14, 4509–4521 (1994).

    Article  CAS  Google Scholar 

  20. Seuningen, I., Ostrowski, J., Bustelo, X., Sleath, P. & Bomsztyk, K. J. Biol. Chem. 270, 26976–26985 (1995).

    Article  Google Scholar 

  21. Schullery, D. et al. J. Biol. Chem. 274, 15101–15109 (1999).

    Article  CAS  Google Scholar 

  22. Shah, K., Liu, Y., Deirmengian, C. & Shokat, K. M. Proc. Natl Acad. Sci. USA 94, 3565–3570 (1997).

    Article  CAS  Google Scholar 

  23. Liu, Y., Shah, K., Yang, F., Witucki, L. & Shokat, K. M. Chem. Biol. 5, 91–102 (1998).

    Article  CAS  Google Scholar 

  24. Gillespie, P. G., Gillespie, S. K., Mercer, J. A., Shah, K. & Shokat, K. M. J. Biol. Chem. 29, 31373–31381 (1999).

    Article  Google Scholar 

  25. van der Houven van Oordt, W. et al. J. Cell. Biol. 149, 307–316 (2000).

    Article  CAS  Google Scholar 

  26. Ohno, M., Segref, A., Bachi, A., Wilm, M. & Mattaj, I. W. Cell 101, 187–198 (2000).

    Article  CAS  Google Scholar 

  27. Kim, J., Hahm, B., Kim, Y., Choi, M. & Jang, S. J. Mol. Biol. 298, 395–405 (2000).

    Article  CAS  Google Scholar 

  28. Ostareck-Lederer, A., Ostareck, D. H. & Hentze, M. W. Trends Biochem. Sci. 11, 409–411 (1998).

    Article  Google Scholar 

  29. Jayawickreme, S., Gray, T., Nettesheim, P. & Eling, T. Am. J. Physiol. 276, 596–603 (1999).

    Google Scholar 

  30. Brinckmann, R. et al. Biochem. J. 318, 305–312 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Morgan and J. Blethrow for advice, M. Karin for JNKK2(CAA), S. Aaronson for MEK-EL constructs, and G. Dreyfuss for monoclonal antibodies against K protein. We also thank S. Phinol-Roma and members of the Ronai laboratory for advice and comments on the manuscript. This work was supported by grants from the National Institutes of Health.

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Correspondence to Ze'ev Ronai.

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Habelhah, H., Shah, K., Huang, L. et al. ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nat Cell Biol 3, 325–330 (2001). https://doi.org/10.1038/35060131

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