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A direct link of the Mos–MAPK pathway to Erp1/Emi2 in meiotic arrest of Xenopus laevis eggs


In vertebrates, unfertilized eggs (or mature oocytes) are arrested at metaphase of meiosis II by a cytoplasmic activity called cytostatic factor (CSF)1. The classical Mos–MAPK pathway has long been implicated in CSF arrest of vertebrate eggs, but exactly how it exerts CSF activity remains unclear2,3,4. Recently, Erp1 (also called Emi2), an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) required for degradation of the mitotic regulator cyclin B (ref. 5), has also been shown to be a component of CSF in both Xenopus and mice6,7,8. Erp1 is destroyed on fertilization or egg activation9,10, like Mos11. However, despite these similarities the Mos–MAPK (mitogen-activated protein kinase) pathway and Erp1 are thought to act rather independently in CSF arrest3,6,8. Here, we show that p90rsk, the kinase immediately downstream from Mos–MAPK, directly targets Erp1 for CSF arrest in Xenopus oocytes. Erp1 is synthesized immediately after meiosis I, and the Mos–MAPK pathway or p90rsk is essential for CSF arrest by Erp1. p90rsk can directly phosphorylate Erp1 on Ser 335/Thr 336 both in vivo and in vitro, and upregulates both Erp1 stability and activity. Erp1 is also present in early embryos, but has little CSF activity owing, at least in part, to the absence of p90rsk activity. These results clarify the direct link of the classical Mos–MAPK pathway to Erp1 in meiotic arrest of vertebrate oocytes.

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Figure 1: Requirement of the MosMAPK pathway for Erp1 activity.
Figure 2: Phoshorylation of Erp1 by p90rsk.
Figure 3: Upregulation of Erp1 stability and activity by Ser 335/Thr 336 phosphorylation.
Figure 4: Model of the relationship between the MosMAPK pathway and Erp1 in metaphase II arrest of Xenopus oocytes.


  1. Masui, Y. & Markert, C. L. Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. J. Exp. Zool. 177, 129–145 (1971)

    CAS  Article  Google Scholar 

  2. Sagata, N. Meiotic metaphase arrest in animal oocytes: its mechanisms and biological significance. Trends Cell Biol. 6, 22–28 (1996)

    CAS  Article  Google Scholar 

  3. Tunquist, B. J. & Maller, J. L. Under arrest: cytostatic factor (CSF)-mediated metaphase arrest in vertebrate eggs. Genes Dev. 17, 683–710 (2003)

    CAS  Article  Google Scholar 

  4. Brunet, S. & Maro, B. Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space. Reproduction 130, 801–811 (2005)

    CAS  Article  Google Scholar 

  5. Peters, J. M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nature Rev. Mol. Cell Biol. 7, 644–656 (2006)

    CAS  Article  Google Scholar 

  6. Schmidt, A. et al. Xenopus polo-like kinase Plx1 regulates XErp1, a novel inhibitor of APC/C activity. Genes Dev. 19, 502–513 (2005)

    CAS  Article  Google Scholar 

  7. Tung, J. J. et al. A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus eggs. Proc. Natl Acad. Sci. USA 102, 4318–4323 (2005)

    ADS  CAS  Article  Google Scholar 

  8. Shoji, S. et al. Mammalian Emi2 mediates cytostatic arrest and transduces the signal for meiotic exit via Cdc20. EMBO J. 25, 834–845 (2006)

    CAS  Article  Google Scholar 

  9. Rauh, N. R., Schmidt, A., Bormann, J., Nigg, E. A. & Mayer, T. U. Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature 437, 1048–1052 (2005)

    ADS  CAS  Article  Google Scholar 

  10. Hansen, D. V., Tung, J. J. & Jackson, P. K. CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc. Natl Acad. Sci. USA 103, 608–613 (2006)

    ADS  CAS  Article  Google Scholar 

  11. Watanabe, N., Hunt, T., Ikawa, Y. & Sagata, N. Independent inactivation of MPF and cytostatic factor (Mos) upon fertilization of Xenopus eggs. Nature 352, 247–248 (1991)

    ADS  CAS  Article  Google Scholar 

  12. Ohe, M., Inoue, D., Kanemori, Y. & Sagata, N. Erp1/Emi2 is essential for the meiosis I to meiosis II transition in Xenopus oocytes. Dev. Biol. 303, 157–164 (2007)

    CAS  Article  Google Scholar 

  13. Liu, J., Grimison, B., Lewellyn, A. L. & Maller, J. L. The anaphase-promoting complex/cyclosome inhibitor Emi2 is essential for meiotic but not mitotic cell cycles. J. Biol. Chem. 281, 34736–34741 (2006)

    CAS  Article  Google Scholar 

  14. Furuno, N. et al. Suppression of DNA replication via Mos function during meiotic divisions in Xenopus oocytes. EMBO J. 13, 2399–2410 (1994)

    CAS  Article  Google Scholar 

  15. Gross, S. D. et al. The critical role of the MAP kinase pathway in meiosis II in Xenopus oocytes is mediated by p90Rsk. Curr. Biol. 10, 430–438 (2000)

    CAS  Article  Google Scholar 

  16. Sagata, N., Watanabe, N., Vande Woude, G. F. & Ikawa, Y. The c-mos proto-oncogene product is a cytostatic factor responsible for meiotic arrest in vertebrate eggs. Nature 342, 512–518 (1989)

    ADS  CAS  Article  Google Scholar 

  17. Murakami, M. S., Copeland, T. D. & Vande Woude, G. F. Mos positively regulates Xe-Wee1 to lengthen the first mitotic cell cycle of Xenopus. Genes Dev. 13, 620–631 (1999)

    CAS  Article  Google Scholar 

  18. Bhatt, R. R. & Ferrell, J. E. The protein kinase p90 rsk as an essential mediator of cytostatic factor activity. Science 286, 1362–1365 (1999)

    CAS  Article  Google Scholar 

  19. Gross, S. D., Schwab, M. S., Lewellyn, A. L. & Maller, J. L. Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk. Science 286, 1365–1367 (1999)

    CAS  Article  Google Scholar 

  20. Reimann, J. D. & Jackson, P. K. Emi1 is required for cytostatic factor arrest in vertebrate eggs. Nature 416, 850–854 (2002)

    ADS  CAS  Article  Google Scholar 

  21. Furuno, N., Ogawa, Y., Iwashita, J., Nakajo, N. & Sagata, N. Meiotic cell cycle in Xenopus oocytes is independent of cdk2 kinase. EMBO J. 16, 3860–3865 (1997)

    CAS  Article  Google Scholar 

  22. Yamamoto, T. M., Iwabuchi, M., Ohsumi, K. & Kishimoto, T. APC/C-Cdc20-mediated degradation of cyclin B participates in CSF arrest in unfertilized Xenopus eggs. Dev. Biol. 279, 345–355 (2005)

    CAS  Article  Google Scholar 

  23. Smith, J. A. et al. Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res. 65, 1027–1034 (2005)

    CAS  Article  Google Scholar 

  24. Masui, Y. The elusive cytostatic factor in the animal egg. Nature Rev. Mol. Cell Biol. 1, 228–232 (2000)

    CAS  Article  Google Scholar 

  25. Madgwick, S., Hansen, D. V., Levasseur, M., Jackson, P. K. & Jones, K. T. Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis. J. Cell Biol. 174, 791–801 (2006)

    CAS  Article  Google Scholar 

  26. Dumont, J., Umbhauer, M., Rassinier, P., Hanauer, A. & Verlhac, M. H. p90Rsk is not involved in cytostatic factor arrest in mouse oocytes. J. Cell Biol. 169, 227–231 (2005)

    CAS  Article  Google Scholar 

  27. Lefebvre, C. et al. Meiotic spindle stability depends on MAPK-interacting and spindle-stabilizing protein (MISS), a new MAPK substrate. J. Cell Biol. 157, 603–613 (2002)

    CAS  Article  Google Scholar 

  28. Hauge, C. & Frodin, M. RSK and MSK in MAP kinase signalling. J. Cell Sci. 119, 3021–3023 (2006)

    CAS  Article  Google Scholar 

  29. Inoue, D. & Sagata, N. The Polo-like kinase Plx1 interacts with and inhibits Myt1 after fertilization of Xenopus eggs. EMBO J. 24, 1057–1067 (2005)

    CAS  Article  Google Scholar 

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We thank members of the Sagata laboratory for discussions and K. Gotoh for typing the manuscript. This work was supported by a scientific grant from the CREST Research Project of Japan Science and Technology Agency to N.S.

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Correspondence to Noriyuki Sagata.

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Inoue, D., Ohe, M., Kanemori, Y. et al. A direct link of the Mos–MAPK pathway to Erp1/Emi2 in meiotic arrest of Xenopus laevis eggs. Nature 446, 1100–1104 (2007).

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