Regulation of MBK-2/DYRK by CDK-1 and the pseudophosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition

Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, Center for Cell Dynamics, Johns Hopkins School of Medicine, 725 N. Wolfe Street, PCTB 706, Baltimore, MD 21205, USA.
Cell (Impact Factor: 32.24). 10/2009; 139(3):560-72. DOI: 10.1016/j.cell.2009.08.047
Source: PubMed


DYRKs are kinases that self-activate in vitro by autophosphorylation of a YTY motif in the kinase domain, but their regulation in vivo is not well understood. In C. elegans zygotes, MBK-2/DYRK phosphorylates oocyte proteins at the end of the meiotic divisions to promote the oocyte-to-embryo transition. Here we demonstrate that MBK-2 is under both positive and negative regulation during the transition. MBK-2 is activated during oocyte maturation by CDK-1-dependent phosphorylation of serine 68, a residue outside of the kinase domain required for full activity in vivo. The pseudotyrosine phosphatases EGG-4 and EGG-5 sequester activated MBK-2 until the meiotic divisions by binding to the YTY motif and inhibiting MBK-2's kinase activity directly, using a mixed-inhibition mechanism that does not involve tyrosine dephosphorylation. Our findings link cell-cycle progression to MBK-2/DYRK activation and the oocyte-to-embryo transition.

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    • "How do MEX-5/6 anchor PLK-1 in the anterior? The minibrain kinase, MBK-2, which is activated at the end of meiosis II by CDK-1 (figure 2b) [71], phosphorylates MEX-5 on a polo-docking site [67]. Once phosphorylated, MEX-5 interacts with the PLK-1-PBD and thereby anchors PLK-1 in the anterior part of the embryo. "
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    ABSTRACT: Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression.
    Open Biology 08/2013; 3(8):130083. DOI:10.1098/rsob.130083 · 5.78 Impact Factor
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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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