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: 31.96). 10/2009; 139(3):560-72. DOI: 10.1016/j.cell.2009.08.047
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pseudophosphatases and pseudokinases are increasingly viewed as integral elements of signaling pathways, and there is mounting evidence that they have frequently retained the ability to interact with cellular 'substrates', and can exert important roles in different diseases. However, these pseudoenzymes have traditionally received scant attention compared to classical kinases and phosphatases. In this review we explore new findings in the emerging pseudokinase and pseudophosphatase fields, and discuss their different modes of action which include exciting new roles as scaffolds, anchors, spatial modulators, traps, and ligand-driven regulators of canonical kinases and phosphatases. Thus, it is now apparent that pseudokinases and pseudophosphatases both support and drive a panoply of signaling networks. Finally, we highlight recent evidence on their involvement in human pathologies, marking them as potential novel drug targets.
    Trends in cell biology 05/2014; · 12.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein Tyrosine Phosphatases (PTPs) are key enzymes in the regulation of cellular homeostasis and signalling pathways. Strikingly, not all PTPs bear enzymatic activity. A considerable fraction of PTPs are enzymatically inactive and are known as pseudophosphatases. Despite the lack of activity they execute pivotal roles in development, cell biology and human disease. The present review is focused on the methods used to identify pseudophosphatases, their targets, and physiological roles. We present a strategy for detailed enzymatic analysis of inactive PTPs, regulation of inactive PTP domains and identification of binding partners. Furthermore, we provide a detailed overview of human pseudophosphatases and discuss their regulation of cellular processes and function in human pathologies.
    Methods 09/2013; · 3.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Screening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole genome sequencing and single nucleotide polymorphism mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in Caenorhabditis elegans (Doitsidou et al. 2010). We show here that WGS/SNP mapping is an efficient method to map suppressor mutations, without the need for prior phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell cycle regulators that extend the timing of the oocyte-to-zygote transition.
    G3-Genes Genomes Genetics 12/2013; · 1.79 Impact Factor


Available from