The Mos-p90rsk-Erp1 MAPK signaling cascade is required for establishing and maintaining cytostatic factor (CSF)-mediated cell cycle arrest in mature Xenopus laevis oocytes.
Cytostatic factor (CSF) mediates prolonged vertebrate cell cycle arrest at metaphase of meiosis II. CSF is a cytoplasmic complex that contains the kinases calmodulin-dependent protein kinase II (CaMKII), Mos, Mek, Erk and p90rsk, as well as other as yet unknown proteins. CSF-mediated arrest is maintained through constitutive inhibition of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). While a role for the APC/C inhibitor Erp1/Emi2 in establishing and maintaining CSF arrest was recently uncovered, the biological link between Erp1 and other components of CSF has not been defined. Two reports by Inoue et al. and Nishiyama et al. in Nature now show that Mos activates p90rsk in Xenopus oocytes, which in turn directly phosphorylates and activates Erp1 to promote CSF-mediated cell cycle arrest.
Inoue et al. determined that p90rsk phosphorylates Erp1 at Ser335 and Thr336 in vitro and in vivo. Phosphorylation at both sites synergistically enhanced Erp1 protein stability and activity. Thus, dual phosphorylation of Erp1 was required for the establishment and maintenance of CSF arrest. Pharmacologic inhibition of p90rsk resulted in the degradation of Erp1, underscoring the importance of p90rsk activity in Erp1 function.
The observations of Nishiyama et al. confirmed and extended these results by showing that in addition to Ser335, phosphorylation of Ser342 and Ser344 on Erp1 was also required for the maintenance of meiosis II arrest. Genetic depletion of p90rsk2 in Xenopus oocytes reduced phosphorylation of exogenous Erp1, an effect that was restored by addition of p90rsk or constitutively active p90rsk2. Furthermore, the authors found that phosphorylated Erp1 bound to APC/C through its C-terminal "destruction box.".
Taken together, these results indicate that p90rsk phosphorylation of Erp1 is required for Erp1-mediated inhibition of APC/C and subsequent cell cycle arrest. This adds a new component to the amphibian CSF complex, which now consists of a minimum of CaMKII, Mos, Mek, Erk, p90rsk and Erp1. The Mos-p90rsk-Erp1 MAPK pathway is essential for CSF-mediated arrest, but other factors undoubtedly impinge upon the pathway to promote and maintain cell cycle arrest. In mammalian oocytes, CSF-mediated arrest occurs via a p90rsk-independent mechanism, although the factors required for cell cycle arrest are still unknown. The involvement of MAPK kinases in maintaining Xenopus meiosis II arrest suggest that other kinases downstream of Mos or p90rsk, such as MEK1 or MSK, may be important in mediating mammalian CSF arrest.
Emily J. Chenette Signaling Gateway
References
Daigo Inoue, Munemichi Ohe, Yoshinori Kanemori, Toshiya Nobui & Noriyuki Sagata. A direct link of the Mos-MAPK pathway to Erp1/Emi2 in meiotic arrest of Xenopus laevis eggs. Nature446, 1100-1104 (2007) | Article | PubMed |
Tomoko Nishiyama, Keita Ohsumi & Takeo Kishimoto. Phosphorylation of Erp1 by p90rsk is required for cytostatic factor arrest in Xenopus laevis eggs. Nature446, 1096-1099 (2007) | Article | PubMed |
