Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Phosphorylation of CPE binding factor by Eg2 regulates translation of c-mos mRNA

Nature volume 404, pages 302–307 (2000)Cite this article

Abstract

Full-grown Xenopus oocytes arrest at the G2/M border of meiosis I. Progesterone breaks this arrest, leading to the resumption of the meiotic cell cycles and maturation of the oocyte into a fertilizable egg. In these oocytes, progesterone interacts with an unidentified surface-associated receptor, which induces a non-transcriptional signalling pathway that stimulates the translation of dormant c-mos messenger RNA. Mos, a mitogen-activated protein (MAP) kinase kinase kinase, indirectly activates MAP kinase, which in turn leads to oocyte maturation. The translational recruitment of c- mos and several other mRNAs is regulated by cytoplasmic polyadenylation, a process that requires two 3′ untranslated regions, the cytoplasmic polyadenylation element (CPE) and the polyadenylation hexanucleotide AAUAAA1,2,3,4. Although the signalling events that trigger c-mos mRNA polyadenylation and translation are unclear, they probably involve the activation of CPEB, the CPE binding factor5,6. Here we show that an early site-specific phosphorylation of CPEB is essential for the polyadenylation of c-mos mRNA and its subsequent translation, and for oocyte maturation. In addition, we show that this selective, early phosphorylation of CPEB is catalysed by Eg2, a member of the Aurora family of serine/threonine protein kinases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CPEB is phosphorylated early after progesterone stimulation and hyperphosphorylated at maturation.
Figure 2: Phosphorylation of Pp1 occurs early after progesterone stimulation and does not require Mos synthesis.
Figure 3: Phosphorylation of CPEB is required for polyadenylation-induced translation.
Figure 4: Eg2 phosphorylates CPEB at Ser 174.

Similar content being viewed by others

References

  1. Hake, L. E. & Richter, J. D. Translational regulation of maternal mRNA. Biochim. Biophys. Acta 1332, M31– M38 (1997).

    CAS  PubMed  Google Scholar 

  2. Fox, C. A., Sheets, M. D., Wahle, E. & Wickens, M. P. Polyadenylation of maternal mRNA during oocyte maturation: poly(A) addition in vitro requires a regulated RNA binding activity and a poly(A) polymerase. EMBO J. 11, 5021–5032 ( 1992).

    Article  CAS  Google Scholar 

  3. McGrew, L. L., Dworkin-Rastl, E., Dworkin, M. B. & Richter, J. D. Poly(A) elongation during Xenopus oocyte maturation is required for translational recruitment and is mediated by a short sequence element. Gene Dev. 3, 803–815 ( 1989).

    Article  CAS  Google Scholar 

  4. McGrew, L. L. & Richter, J. D. Translational control by cytoplasmic polyadenylation during Xenopus oocyte maturation: characterization of cis and trans elements and regulation by cyclin/MPF. EMBO J. 9, 3743–3751 ( 1990).

    Article  CAS  Google Scholar 

  5. Hake, L. E. & Richter, J. D. CPEB is a specificity factor that mediates cytoplasmic polyadenylation during Xenopus oocyte maturation. Cell 79, 617–627 (1994).

    Article  CAS  Google Scholar 

  6. Stebbins-Boaz, B., Hake, L. E. & Richter, J. D. CPEB controls the cytoplasmic polyadenylation of cyclin, Cdk2 and c-mos mRNAs and is necessary for oocyte maturation in Xenopus. EMBO J. 15, 2582– 2592 (1996).

    Article  CAS  Google Scholar 

  7. Paris, J., Swenson, K., Piwnica-Worms, H. & Richter, J. D. Maturation-specific polyadenylation: in vitro activation by p34 cdc2 and phosphorylation of a 58-kD CPE-binding protein. Genes Dev. 5, 1697–1708 (1991).

    Article  CAS  Google Scholar 

  8. De Moor, C. H. & Richter, J. D. The mos pathway regulates cytoplasmic polyadenylation in Xenopus oocytes. Mol. Cell. Biol. 17, 6419–6426 ( 1997).

    Article  CAS  Google Scholar 

  9. Ballantyne, S., Daniel, D. L. Jr & Wickens, M. A dependent pathway of cytoplasmic polyadenylation reactions linked to cell cycle control by c-mos and CDK1 activation. Mol. Biol. Cell 8, 1633– 1648 (1997).

    Article  CAS  Google Scholar 

  10. Katsu, Y., Minshall, N., Nagahama, Y. & Standart, N. Ca2+ is required for phosphorylation of clam p82/CPEB in vitro: implications for dual and independent roles of MAP and Cdc2 kinases. Dev. Biol. 209, 186–199 (1999).

    Article  CAS  Google Scholar 

  11. De Moor, C. H. & Richter, J. D. Cytoplasmic polyadenylation elements mediate masking and unmasking of cyclin B1 mRNA. EMBO J. 18, 2294–2303 (1999).

    Article  CAS  Google Scholar 

  12. Andresson, T. & Ruderman, J. V. The kinase Eg2 is a component of the Xenopus oocyte progesterone-activated signaling pathway. EMBO J. 17, 5627–5637 ( 1998).

    Article  CAS  Google Scholar 

  13. Glover, D. M., Leibowitz, M. H., McLean, D. A. & Parry, H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95– 105 (1995).

    Article  CAS  Google Scholar 

  14. Francisco, L., Wang, W. & Chan, C. S. Type 1 protein phosphatase acts in opposition to Ipl-1 protein kinase in regulating yeast chromosome segregation. Mol. Cell Biol. 14, 4731–4740 (1994).

    Article  CAS  Google Scholar 

  15. Bischoff, J. R. et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998).

    Article  CAS  Google Scholar 

  16. Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet. 20, 189–193 (1998).

    Article  CAS  Google Scholar 

  17. Sen, S., Zhou, H. & White, R. A. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 14, 2195– 2200 (1997).

    Article  CAS  Google Scholar 

  18. Tatsuka, M. et al. Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res. 58, 4811 –4816 (1998).

    CAS  PubMed  Google Scholar 

  19. Giet, R., Uzbekov, R., Cubizolles, F., Le Guellec, K. & Prigent, C. The Xenopus laevis Aurora-related protein kinase pEg2 associates with and phosphorylates the kinesin-related protein XIEg5. J. Biol. Chem. 274, 15005 –15013 (1999).

    Article  CAS  Google Scholar 

  20. Hake, L. E., Mendez, R. & Richter, J. D. Specificity of RNA binding by CPEB: Requirement for RNA recognition motifs and a novel zinc finger. Mol. Cell. Biol. 18, 685–693 ( 1998).

    Article  CAS  Google Scholar 

  21. Bilger, A., Fox, C. A., Wahle, E. & Wickens, M. Nuclear polyadenylation factors recognize cytoplasmic polyadenylation elements. Genes Dev. 8, 1106–1116 ( 1994).

    Article  CAS  Google Scholar 

  22. Dickson, K. S., Bilger, A., Ballantyne, S. & Wickens, M.P. The cleavage and polyadenylation specificity factor in Xenopus laevis oocytes is a cytoplasmic factor involved in regulated polyadenylation. Mol. Cell. Biol. 19, 5707–5717 (1999).

    Article  CAS  Google Scholar 

  23. Stebbins-Boaz, B., Cao, Q., de Moor, C. H., Mendez, R. & Richter, J. D. Maskin is a CPEB associated factor that transiently interacts with eIF-4E. Mol. Cell 4, 1017 –1027 (1999).

    Article  CAS  Google Scholar 

  24. Boyle, W. J., van der Geer, P. & Hunter, T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 201, 110–149 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. J. Luna for her help with the two-dimensional separation of phospho-peptides, J. Leszyk for amino-acid sequencing, and the W. M. Keck Foundation for support of the Protein Chemistry Facility. We also thank M. Fernandez and members of the Richter laboratory for discussions and critically reading the manuscript. R.M. was supported by a Leukemia Society of America Special Fellow Award and L.E.L. was supported by a National Science Foundation Predoctoral Fellowship. This work was supported by grants from the NIH (to J.V.R. and J.D.R.).

Author information

Author notes

  1. Laura E. Hake

    Present address: Department of Biology, Boston College, Chestnut Hill, Massachusetts, 02167, USA

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, 01655, Massachusetts, USA

    Raul Mendez, Laura E. Hake & Joel D. Richter

  2. Department of Cell Biology, Harvard Medical School, Boston, 02115 , Massachusetts, USA

    Thorkell Andresson, Laurie E. Littlepage & Joan V. Ruderman

Authors
  1. Raul Mendez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura E. Hake
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorkell Andresson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurie E. Littlepage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joan V. Ruderman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joel D. Richter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joel D. Richter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mendez, R., Hake, L., Andresson, T. et al. Phosphorylation of CPE binding factor by Eg2 regulates translation of c-mos mRNA. Nature 404, 302–307 (2000). https://doi.org/10.1038/35005126

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35005126

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing