Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation.
Vertebrate eggs awaiting fertilization are arrested at metaphase of meiosis II by a biochemical activity termed cytostatic factor (CSF). This activity inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that triggers anaphase onset and mitotic/meiotic exit by targeting securin and M-phase cyclins for destruction. On fertilization a transient rise in free intracellular calcium causes release from CSF arrest and thus APC/C activation. Although it has previously been shown that calcium induces the release of APC/C from CSF inhibition through calmodulin-dependent protein kinase II (CaMKII), the relevant substrates of this kinase have not been identified. Recently, we characterized XErp1 (Emi2), an inhibitor of the APC/C and key component of CSF activity in Xenopus egg extract. Here we show that calcium-activated CaMKII triggers exit from meiosis II by sensitizing the APC/C inhibitor XErp1 for polo-like kinase 1 (Plx1)-dependent degradation. Phosphorylation of XErp1 by CaMKII leads to the recruitment of Plx1 that in turn triggers the destruction of XErp1 by phosphorylating a site known to serve as a phosphorylation-dependent degradation signal. These results provide a molecular explanation for how the fertilization-induced calcium increase triggers exit from meiosis II.
Rauh
Nadine R
NR
Chemical Biology, Independent Research Group, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Schmidt
Andreas
A
Bormann
Jenny
J
Nigg
Erich A
EA
Mayer
Thomas U
TU
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism*; D005306:Fertilization / Q000502:physiology; D008540:Meiosis / Q000187:drug effects*; D008954:Models, Biological; D010063:Ovum / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017231:Proto-Oncogene Proteins c-mos / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D064173:Anaphase-Promoting Complex-Cyclosome; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D017346:Protein Serine-Threonine Kinases; D017231:Proto-Oncogene Proteins c-mos; D043743:Ubiquitin-Protein Ligase Complexes; D029867:Xenopus Proteins; C498166:FBXO43 protein, Xenopus; C101085:Plk1 protein, Xenopus; D000097869:Polo-Like Kinase 1