Regulation of MBK-2/DYRK by CDK-1 and the pseudophosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.
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.
Cheng
Ken Chih-Chien
KC
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.
Klancer
Richard
R
Singson
Andrew
A
Seydoux
Geraldine
G
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; C545208:EGG-4 protein, C elegans; C545209:EGG-5 protein, C elegans; C478059:MBK-2 protein, C elegans; D011505:Protein-Tyrosine Kinases; D016203:CDC2 Protein Kinase