The C. elegans DYRK Kinase MBK-2 Marks Oocyte Proteins for Degradation in Response to Meiotic Maturation

Howard Hughes Medical Institute and Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, 725 N. Wolfe St., PCTB 706, Baltimore, Maryland 21205, USA.
Current Biology (Impact Factor: 9.57). 02/2006; 16(1):56-62. DOI: 10.1016/j.cub.2005.11.063
Source: PubMed


The oocyte-to-embryo transition transforms a differentiated germ cell into a totipotent zygote capable of somatic development. In C. elegans, several oocyte proteins, including the meiotic katanin subunit MEI-1 and the oocyte maturation protein OMA-1, must be degraded during this transition . Degradation of MEI-1 and OMA-1 requires the dual-specificity YAK-1-related (DYRK) kinase MBK-2 . Here, we demonstrate that MBK-2 directly phosphorylates MEI-1 and OMA-1 in vitro and that this activity is essential for degradation in vivo. Phosphorylation of MEI-1 by MBK-2 reaches maximal levels after the meiotic divisions, immediately preceding MEI-1 degradation. MEI-1 phosphorylation and degradation still occur in spe-9 eggs, which undergo meiotic maturation and exit in the absence of fertilization . In contrast, MEI-1 phosphorylation and degradation are blocked in cell-cycle mutants that arrest during the meiotic divisions, and are accelerated in wee-1.3(RNAi) oocytes, which prematurely enter meiotic M phase (A. Golden, personal communication). A GFP:MBK-2 fusion relocalizes from the cortex to the cytoplasm during the meiotic divisions, and this relocalization also depends on cell-cycle progression. Our findings suggest that regulators of meiotic M phase activate a remodeling program, independently of fertilization, to prepare eggs for embryogenesis.

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    • "This transcriptional repression function of OMA proteins is likely not relevant for the regulation of meiotic maturation because this activity only manifests upon phosphorylation by the dual-speci fi city tyrosine-phosphorylation-regulated protein kinase MBK-2. MBK-2 only becomes active in oocytes upon meiotic maturation (Stitzel et al. 2006 ; Cheng et al. 2009 ) . In fact, phosphorylation of OMA-1 by MBK-2 was shown to displace SPN-2 from the zif-1 3-UTR, thereby alleviating translational repression (Guven-Ozkan et al. 2010 ) . "
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    ABSTRACT: In sexually reproducing animals, oocytes arrest at diplotene or diakinesis and resume meiosis (meiotic maturation) in response to hormones. Chromosome segregation errors in female meiosis I are the leading cause of human birth defects, and age-related changes in the hormonal environment of the ovary are a suggested cause. Caenorhabditis elegans is emerging as a genetic paradigm for studying hormonal control of meiotic maturation. The meiotic maturation processes in C. elegans and mammals share a number of biological and molecular similarities. Major sperm protein (MSP) and luteinizing hormone (LH), though unrelated in sequence, both trigger meiotic resumption using somatic Gα(s)-adenylate cyclase pathways and soma-germline gap-junctional communication. At a molecular level, the oocyte responses apparently involve the control of conserved protein kinase pathways and post-transcriptional gene regulation in the oocyte. At a cellular level, the responses include cortical cytoskeletal rearrangement, nuclear envelope breakdown, assembly of the acentriolar meiotic spindle, chromosome segregation, and likely changes important for fertilization and the oocyte-to-embryo transition. This chapter focuses on signaling mechanisms required for oocyte growth and meiotic maturation in C. elegans and discusses how these mechanisms coordinate the completion of meiosis and the oocyte-to-embryo transition.
    Advances in Experimental Medicine and Biology 01/2013; 757:277-320. DOI:10.1007/978-1-4614-4015-4_10 · 1.96 Impact Factor
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    • "Second, a phosphorylation event that marks MEI-1 for degradation is also developmentally regulated. Degradation of MEI-1 requires phosphorylation at serine 92 by the MBK-2 kinase, which itself is activated at meiosis II (more on MBK-2 activation below) (Cheng et al. 2009 ; Pang et al. 2004 ; Pellettieri et al. 2003 ; Quintin et al. 2003 ; Stitzel et al. 2006 ) . Third, translation of maternal mei-1 mRNA, which is still present in the early embryo, is actively repressed in order to prevent more MEI-1 from being made. "
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    ABSTRACT: The oocyte-to-embryo transition refers to the process whereby a fully grown, relatively quiescent oocyte undergoes maturation, fertilization, and is converted into a developmentally active, mitotically dividing embryo, arguably one of the most dramatic transitions in biology. This transition occurs very rapidly in Caenorhabditis elegans, with fertilization of a new oocyte occurring every 23 min and the first mitotic division occurring 45 min later. Molecular events regulating this transition must be very precisely timed. This chapter reviews our current understanding of the coordinated temporal regulation of different events during this transition. We divide the oocyte-to-embryo transition into a number of component processes, which are coordinated primarily through the MBK-2 kinase, whose activation is intimately tied to completion of meiosis, and the OMA-1/OMA-2 proteins, whose expression and functions span multiple processes during this transition. The oocyte-to-embryo transition occurs in the absence of de novo transcription, and all the factors required for the process, whether mRNA or protein, are already present within the oocyte. Therefore, all regulation of this transition is posttranscriptional. The combination of asymmetric partitioning of maternal factors, protein modification-mediated functional switching, protein degradation, and highly regulated translational repression ensure a smooth oocyte-to-embryo transition. We will highlight protein degradation and translational repression, two posttranscriptional processes which play particularly critical roles in this transition.
    Advances in Experimental Medicine and Biology 01/2013; 757:351-72. DOI:10.1007/978-1-4614-4015-4_12 · 1.96 Impact Factor
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    • "Similarly, in response to DNA damage mammalian DYRK2 translocates to the nucleus and phosphorylates p53 thereby initiating an apoptotic response [31]. The activity of the C. elegans DYRK family member, MBK-2, is carefully regulated during the oocyte-to-embryo transition through a series of actions involving timely relocalization of the kinase thus providing access to relevant substrates [36], inhibitory protein complexes involving the pseudophosphatases EGG-3, EGG-4 and EGG-5 [36]–[38], and finally through direct phosphorylation of MBK-2 by the cell cycle kinase, CDK-1 [37]. However, the best understood mechanism for regulating the catalytic activity of the kinase is phosphorylation of the DYRK activation loop. "
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    ABSTRACT: DYRK-family kinases employ an intramolecular mechanism to autophosphorylate a critical tyrosine residue in the activation loop. Once phosphorylated, DYRKs lose tyrosine kinase activity and function as serine/threonine kinases. DYRKs have been characterized in organisms from yeast to human; however, all entities belong to the Unikont supergroup, only one of five eukaryotic supergroups. To assess the evolutionary age and conservation of the DYRK intramolecular kinase-activation mechanism, we surveyed 21 genomes representing four of the five eukaryotic supergroups for the presence of DYRKs. We also analyzed the activation mechanism of the sole DYRK (class 2 DYRK) present in Trypanosoma brucei (TbDYRK2), a member of the excavate supergroup and separated from Drosophila by ∼850 million years. Bioinformatics showed the DYRKs clustering into five known subfamilies, class 1, class 2, Yaks, HIPKs and Prp4s. Only class 2 DYRKs were present in all four supergroups. These diverse class 2 DYRKs also exhibited conservation of N-terminal NAPA regions located outside of the kinase domain, and were shown to have an essential role in activation loop autophosphorylation of Drosophila DmDYRK2. Class 2 TbDYRK2 required the activation loop tyrosine conserved in other DYRKs, the NAPA regions were critical for this autophosphorylation event, and the NAPA-regions of Trypanosoma and human DYRK2 complemented autophosphorylation by the kinase domain of DmDYRK2 in trans. Finally, sequential deletion analysis was used to further define the minimal region required for trans-complementation. Our analysis provides strong evidence that class 2 DYRKs were present in the primordial or root eukaryote, and suggest this subgroup may be the oldest, founding member of the DYRK family. The conservation of activation loop autophosphorylation demonstrates that kinase self-activation mechanisms are also primitive.
    PLoS ONE 01/2012; 7(1):e29702. DOI:10.1371/journal.pone.0029702 · 3.23 Impact Factor
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