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

Abstract

The transition of oocytes from meiosis I (MI) to meiosis II (MII) requires partial cyclin B degradation to allow MI exit without S phase entry. Rapid reaccumulation of cyclin B allows direct progression into MII, producing a cytostatic factor (CSF)-arrested egg. It has been reported that dampened translation of the anaphase-promoting complex (APC) inhibitor Emi2 at MI allows partial APC activation and MI exit. We have detected active Emi2 translation at MI and show that Emi2 levels in MI are mainly controlled by regulated degradation. Emi2 degradation in MI depends not on Ca2+/calmodulin-dependent protein kinase II (CaMKII), but on Cdc2-mediated phosphorylation of multiple sites within Emi2. As in MII, this phosphorylation is antagonized by Mos-mediated recruitment of PP2A to Emi2. Higher Cdc2 kinase activity in MI than MII allows sufficient Emi2 phosphorylation to destabilize Emi2 in MI. At MI anaphase, APC-mediated degradation of cyclin B decreases Cdc2 activity, enabling Cdc2-mediated Emi2 phosphorylation to be successfully antagonized by Mos-mediated PP2A recruitment. These data suggest a model of APC autoinhibition mediated by stabilization of Emi2; Emi2 proteins accumulate at MI exit and inhibit APC activity sufficiently to prevent complete degradation of cyclin B, allowing MI exit while preventing interphase before MII entry.

Mos limits the number of meiotic divisions in urochordate eggs

“…This is consistent with Mos-induced stabilization of MPF (Tachibana et al, 2000;Dupre et al, 2002;Kishimoto, 2003;Tang et al, 2008) and causes re-entry into additional rounds of meiotic M phase in urochordates (Fig. 6).…”

“…This is not the case for meiosis. During maternal meiosis even though cyclin B destruction ensures exit from meiosis I in both urochordates and vertebrates oocytes, MPF activity comes back to drive entry into meiosis II (Levasseur and McDougall, 2000;Dupre et al, 2002;Herbert et al, 2003;Madgwick et al, 2006;Tang et al, 2008). This is probably due to the precocious inhibition of APC/C after anaphase I thereby allowing for early accumulation of cyclin B during interkinesis (Iwabuchi et al, 2000;Madgwick et al, 2006;Tang et al, 2008).…”

Phospho-Signaling at Oocyte Maturation and Fertilization: Set Up for Embryogenesis and Beyond Part II. Kinase Regulators and Substrates

“…Emi1 has been identified first as a negative regulator of APC/C in Xenopus eggs and cell-free extracts (Reimann et al 2001a;Reimann et al 2001b;Reimann and Jackson 2002). Thereafter, an Emi1-related protein named Emi2/xErp1 has been identified and characterized as an essential component of CSF inhibition of APC/C (Hansen et al 2006;Liu and Maller 2005;Rauh et al 2005;Tang et al 2008;Tung et al 2005;Wu et al 2007a;Wu et al 2007b). In the current scenario, CSF arrest by Emi2/xErp1 of APC/C involves recruitment of PP2A to the Rsk-phosphorylated Emi2/xErp1 (this phosphorylation has stabilizing effect on Emi2/xErp1) and its phosphatase action on other phosphates in Emi2/xErp1 catalyzed by Cdc2/cyclin B complex (this phosphorylation weakens Emi2/xErp1).…”

Phospho-Signaling at Oocyte Maturation and Fertilization: Set Up for Embryogenesis and Beyond Part I. Protein Kinases

“…Kinase activity of cdc/CDK/MPF has been sometimes regarded as "histone H1 kinase (H1K or HH1K)" because of its in vitro evaluation. Cellular targets of cdc/CDK kinases include aurora kinase and Emi2, which are implicated in chromosomal integrity and meiotic arrest, respectively (Anger et al 2004;Castilho et al 2009;Culp and Musci 1999;Eckberg 1997;Edgecombe et al 1991;Ferrell 1999;Ferrell et al 1991;Gavin et al 1999;Grieco et al 1996;Gutierrez et al 2006;Karaiskou et al 1998;Karaiskou et al 2004;Katsu et al 1999;Kume et al 2007;Kuo et al 2011;Lohka et al 1988;Masui 2000;Maton et al 2005;Maton et al 2003;Meijer et al 1989a;Meijer et al 1991;Meijer et al 1989b;Palmer et al 1998;Qian et al 2001;Rime et al 1994;Ruiz et al 2008;Sakamoto et al 1998;Tang et al 2008;Tokmakov et al 2005;Wu et al 2007b;Yu et al 2005;Yu et al 2004).…”

“…Mos contribute in the first cycle of Xenopus embryogenesis (Murakami and Vande Woude 1998) and act like Mos/Raf-1/MAPK pathway (Muslin et al 1993) or without Raf like Mos/MAPK pathway both in Xenopus (Shibuya et al 1996) and mouse (Verlhac et al 1996). Mos is also involved in MAPK cascade in the control of microtubule and chromatin organization during meiosis in mouse oocytes (Chesnel et al 1997;Culp and Musci 1999;Daar et al 1993;Faure et al 1998;Mendez et al 2000;Murakami and Vande Woude 1998;Muslin et al 1993;Shibuya et al 1992;Shibuya et al 1996;Tang et al 2008;Verlhac et al 1996;Wu et al 2007a). …”