Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation

Abstract

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.

Cdc2 and Mos Regulate Emi2 Stability to Promote the Meiosis I–Meiosis II Transition

“…Throughout MI, Emi2 protein undergoes continuous and rapid turnover. Interestingly, we demonstrate that the same degron that controls precipitous degradation of Emi2 at exit from MII also regulates the continuous degradation of Emi2 before MI exit (Rauh et al, 2005). Moreover, this degradation is required to prevent inappropriate MI arrest.…”

“…At fertilization, a transient increase in cellular Ca 2ϩ level activates calmodulin-dependent protein kinase II (CaMKII), which primes Emi2 for docking of the Polo-like kinase 1 (Plx1 in Xenopus) and subsequent Plx1-mediated Emi2 phosphorylation. This creates a phosphodegron for the E3 ligase SCF ␤Trcp , leading to proteasomal degradation (Liu and Maller, 2005;Rauh et al, 2005;Hansen et al, 2006). When Emi2 is degraded, the APC is fully acti-vated, releasing eggs from MII into the first embryonic cell cycle (Wu et al, 2007a).…”

Transitioning from egg to embryo: Triggers and mechanisms of egg activation

“…2B). Degradation of Emi2 relieves the inhibition of the APC so that the APC becomes active (Liu and Maller, 2005;Rauh et al, 2005). The APC is a ubiquitin ligase that targets cell cycle regulators for destruction by the proteasome (reviewed in Castro et al, 2005).…”

Ca2+ signaling differentiation during oocyte maturation

“…CaMKII mediates the meiotic to mitotic transition by inactivating both maturation promoting factor (MPF) and cytostatic factor (CSF; Lorca et al, 1993;Morin et al, 1994;Knott et al, 2006). CaMKII mediates this effect by phosphorylating the APC inhibitor XErp1/Emi2 (Liu and Maller, 2005;Rauh et al, 2005;Hansen et al, 2006). This phosphorylation primes XErp1/Emi2 for phosphorylation by Plx1.…”