A two-step inactivation mechanism of Myt1 ensures CDK1/cyclin B activation and meiosis I entry.
Activation of CDK1 is essential for M-phase entry both in mitosis and meiosis. G2-arrested oocytes contain a pool of CDK1/cyclin B complexes that are maintained inactive because of the phosphorylation of CDK1 on Thr14 and Tyr15 by the Wee1 family protein kinase Myt1, whose inhibition suffices to induce meiosis I entry [1-5]. CDK1/XRINGO and p90Rsk can both phosphorylate and downregulate Myt1 activity in vitro [6, 7]. Here we identify five p90Rsk phosphorylation sites on Myt1 that are different from the CDK1/XRINGO sites, and we show how both kinases synergize during oocyte maturation to inhibit Myt1, ensuring meiotic progression. We found that phosphorylation of Myt1 by CDK1/XRINGO early during oocyte maturation not only downregulates Myt1 kinase activity but also facilitates the recruitment of p90Rsk and further phosphorylation of Myt1. Mutation of the five p90Rsk residues to alanine impairs Myt1 hyperphosphorylation during oocyte maturation and makes Myt1 resistant to the inhibition by p90Rsk. Importantly, Myt1 phosphorylated by p90Rsk does not interact with CDK1/cyclin B, ensuring that the inhibitory phosphorylations of CDK1 cannot take place after meiosis I entry and contributing to the all-or-none meiotic response.
Ruiz
E Josué
EJ
Spanish National Cancer Center, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Vilar
Marçal
M
Nebreda
Angel R
AR
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D008540:Meiosis / Q000502:physiology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D018797:Cell Cycle Proteins; D019926:Cyclin B; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins; C119055:ls27 protein, Xenopus; D011374:Progesterone; C095970:MYT1 kinase, Xenopus; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D016203:CDC2 Protein Kinase