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**22**

**and Substrates**

*University of Dhaka, Dhaka,*

*1Bangladesh 2Japan*

*Kamigamo-Motoyama, Kita-ku, Kyoto*

**Phospho-Signaling at Oocyte Maturation**

**and Beyond Part II. Kinase Regulators**

A.K.M. Mahbub Hasan1, Takashi Matsumoto2,

*Faculty of Life Sciences, Kyoto Sangyo University,*

Shigeru Kihira2, Junpei Yoshida2 and Ken-ichi Sato2,\*

**and Fertilization: Set Up for Embryogenesis**

*1Laboratory of Gene Biology, Department of Biochemistry and Molecular Biology,*

*2Laboratory of Cell Signaling and Development, Department of Molecular Biosciences,*

This chapter is the sequel to the chapter entitled "Phospho-signaling at Oocyte Maturation and Fertilization: Set Up for Embryogenesis and Beyond Part I. Protein Kinases" by Mahbub

**2. Kinase regulators and substrates in oocyte maturation, fertilization and**

Filamentous actin or **F-actin** is a major component of stress fibers and involved in cellular architecture. Its dynamic rearrangement supports not only cellular morphology but also intracellular signal transduction that regulate cell-cell or cell-extracellular matrix interactions, cell motility, and proliferation. Several lines of evidence demonstrate that, in several organisms, oocyte cortical cytoskeleton involving F-actin network undergoes a dynamic rearrangement during meiosis/oocyte maturation and that this is often involving phosphorylation of actin and/or actin-interacting proteins (e.g. ADF/coffilin, see below) catalyzed by PKC (in Tubifex, *Xenopus*) (Capco et al. 1992; Shimizu 1997). In *Drosophila*, PKC phosphorylation of a tumor suppressor protein-homolog named Lgl (lethal (2) giant larvae) is responsible for actin-dependent oocyte polarity formation (Tian and Deng 2008). In mammalian oocytes (rat), F-actin has been implicated in tyrosine kinase-dependent

**1. Introduction**

**activation of development**

Hasan et al.

**2.1 Actin**

 \*

Corresponding Author

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

A.K.M. Mahbub Hasan1, Takashi Matsumoto2, Shigeru Kihira2, Junpei Yoshida2 and Ken-ichi Sato2,\* *1Laboratory of Gene Biology, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 2Laboratory of Cell Signaling and Development, Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 1Bangladesh 2Japan*

## **1. Introduction**

498 Embryogenesis

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2004. SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are expressed in early gestation human placenta and mouse eggs, preimplantation embryos, and

of the c-mos product to associate with and phosphorylate tubulin. Science

This chapter is the sequel to the chapter entitled "Phospho-signaling at Oocyte Maturation and Fertilization: Set Up for Embryogenesis and Beyond Part I. Protein Kinases" by Mahbub Hasan et al.

## **2. Kinase regulators and substrates in oocyte maturation, fertilization and activation of development**

## **2.1 Actin**

Filamentous actin or **F-actin** is a major component of stress fibers and involved in cellular architecture. Its dynamic rearrangement supports not only cellular morphology but also intracellular signal transduction that regulate cell-cell or cell-extracellular matrix interactions, cell motility, and proliferation. Several lines of evidence demonstrate that, in several organisms, oocyte cortical cytoskeleton involving F-actin network undergoes a dynamic rearrangement during meiosis/oocyte maturation and that this is often involving phosphorylation of actin and/or actin-interacting proteins (e.g. ADF/coffilin, see below) catalyzed by PKC (in Tubifex, *Xenopus*) (Capco et al. 1992; Shimizu 1997). In *Drosophila*, PKC phosphorylation of a tumor suppressor protein-homolog named Lgl (lethal (2) giant larvae) is responsible for actin-dependent oocyte polarity formation (Tian and Deng 2008). In mammalian oocytes (rat), F-actin has been implicated in tyrosine kinase-dependent

 \* Corresponding Author

Phospho-Signaling at Oocyte Maturation and Fertilization:

**2.6 Brain-derived neurotrophic factor (BDNF)**

**2.7 Bub1/BubR1**

**2.5 Bad**

Set Up for Embryogenesis and Beyond Part II. Kinase Regulators and Substrates 501

phosphorylation sites in Astrin, causes oocyte meiotic arrest at metaphase I with highly

**Bad** is a member of BH3 (Bcl-2 homology 3) family proteins, the other members of which include Bax, Bak, Bik, Bid and Hrk. While Bcl-2, a firstly identified BH3 and other BH domain (BH1 and BH2)-containing protein, and its relative proteins (e.g. Bcl-xL) act as antiapoptosis components, Bad and other BH3-only proteins participate in pro-apoptotic cellular functions (e.g. activation of caspases) (Danial 2008; Lutz 2000). Most of these antiapoptotic or pro-apoptotic proteins localize to mitochondrial outer membranes and function as a sensor of intracellular damage as well as a trigger of mitochondrial death/survival pathway. Several species ranging from nematode, *Drosophila* and sea invertebrates to vertebrates including mammals undergo germline or ovarian/postovulatory oocyte apoptosis in an age-dependent or -independent manner (Buszczak and Cooley 2000; Chiba 2004; Morita and Tilly 1999). In particular, Bad has recently been identified as a factor for phospho-dependent mechanism of egg apoptosis in *Xenopus* (Du Pasquier et al. 2011). Bad in ovarian oocytes at the first meiotic propahse is negatively regulated by inhibitory phosphorylation on Ser-112 and Ser-136 by unknown mechanism (maybe PKA phosphorylation). Upon oocyte maturation, Bad becomes further phosphorylated on Ser-128 in a CDK- and JNK-dependent manner. The Ser-128 phosphorylation, if it exceeds the extent of those of Ser-112/Ser-136 phosphorylations during a long period of oocyte maturation in the absence of fertilizing sperm, will allow Bad to trigger a mitochondrial apoptotic pathway involving cytochrome c release and caspase activation. Whether normal process of

oocyte maturation and fertilization involves anti-apoptotic mechanism is not known.

**BDNF** is a member of neurotropic family of growth factors that include nerve growth factor (NGF). Its cellular functions are exerted by cell surface receptors such as TrkB, a tyrosine kinase/receptor, and p75 low-affinity NGF receptor (Chao and Hempstead 1995). In mammals including human, ovarian BDNF has been implicated in oogenesis, oocyte maturation, and pre-implantation embryogenesis (Kawamura et al. 2005; Zhang et al. 2010). In vitro maturation of mouse oocytes in the presence of cumulus cells is accompanied by BDNF-dependent activation of Akt/PKB and MAPK and its maintenance has been demonstrated (Zhang et al. 2010). Pharmacological experiments suggest that the Akt/PKB activation involves TrkB function (TrkB-PI3K-PIP3 pathway), while the MAPK does not.

**Bub1** and **BubR1** (Mad3 in yeast, worms and plants) are multidomain-containing proteinserine/threonine kinases that have been characterized as components of the mitotic checkpoint of spindle assembly (Bolanos-Garcia and Blundell 2011). In mouse oocytes, BubR1 is shown to act as a spindle assembly checkpoint protein in the first meiotic arrest (Homer et al. 2009; Jones and Holt 2010; Schwab et al. 2001; Wei et al. 2010). In maturing *Xenopus* oocytes, Bub1 is activated by MAPK-dependent p90Rsk phosphorylation, and is suggested to be involved in spindle assembly checkpoint and, in collaboration with

disordered spindles and disorganized chromosomes (Yuan et al. 2009).

rearrangement of cortical structures (Meng et al. 2006). In unfertilized rat eggs, F-action is in association with PKC and RACKS and thought to suppress the cortical granule to exocytose, and after fertilization, PKC-dependent phosphorylation releases the actin suppression and cortical granule exocytosis occurs (Eliyahu et al. 2005).

## **2.2 ADF/coffilin**

Actin-depolymerizing factor (**ADF**)/**coffilin** are an evolutionarily conserved F-actinbinding protein, whose function is essential for cortical actin cytoskeleton. It is well known that the actin-binding ability of ADF/coffilin can be regulated by its phosphorylation and dephosphorylation (Bamburg et al. 1999). This type of regulation of ADF/coffilin has been reported in maturing oocytes of starfish, where active transport of MPF from nucleus to cytoplasm is required for oocyte maturation (Santella et al. 2003), and dividing embryos of *Xenopus*, where cytokinesis involves the function of ADF/coffilin (Abe et al. 1996; Chiu et al. 2010; Tanaka et al. 2005). In the former case, MPF has been identified as a kinase for ADF/coffilin. In the latter case, protein phosphatase Slingshot is involved in Rho-dependent inactivation of ADF/coffilin, thereby promotes the rearrangement of actin cytoskeleton essential for cytokinesis.

## **2.3 ASIP/PAR-3**

**ASIP**/**PAR-3** (atypical PKC isotype-specific interacting protein/partitioning defective 3) is a PDZ-domain-containing adaptor protein that has been initially identified as a downstream element of PAR-6 in early embryos of the nematode *C. elegans* (Watts et al. 1996). Further studies have demonstrate the importance of PAR3 as an atypical PKC (aPKC)-interacting protein functioning in establishing asymmetric cell division and polarized cell structures in *C. elegans* and *Drosophila* embryos, and mammalian epithelial cells (Joberty et al. 2000). In *Xenopus* immature oocytes, ASIP/PAR-3 is shown to localize to animal hemisphere in association with aPKC, and upon hormone-induced oocyte maturation, aPKC undergoes kinase activity-dependent re-localization. These results suggest a potential role of ASIP/PAR-3 as a regulator and/or substrate of aPKC (Nakaya et al. 2000). Although phosphorylation of Ser-827 in ASIP/PAR-3 by aPKC has been shown in mammalian somatic cell systems (Hirose et al. 2002), its occurrence in oocyte/egg system is not yet demonstrated.

#### **2.4 Astrin**

**Astrin** is a spindle-associated non-motor protein that regulates mitotic cell cycle progression. In the meiosis of mouse oocytes, where centrioles are missing but multiple microtubule-organizing centers (MTOCs) are present, proper lining and segregation of homologous chromosomes and sister chromatids require the precise regulation of MTOCs by centrosomal protein kinases such as Aurora kinase and PLK1. It has been shown that inhibition of Astrin function by RNAi-mediated knockdown or overexpression of a coiledcoil domain of Astrin results in a defect in spindle disorganization, chromosome misalignment and meiosis progression arrest (Yuan et al. 2009). As Astrin localizes to the spindle apparatus, it is suggested that Astrin is a substrate of Aurora/PLK1. In support with this idea, site-directed mutation of Thr-24, Ser-66 or Ser-447, potential PLK1 phosphorylation sites in Astrin, causes oocyte meiotic arrest at metaphase I with highly disordered spindles and disorganized chromosomes (Yuan et al. 2009).

## **2.5 Bad**

500 Embryogenesis

rearrangement of cortical structures (Meng et al. 2006). In unfertilized rat eggs, F-action is in association with PKC and RACKS and thought to suppress the cortical granule to exocytose, and after fertilization, PKC-dependent phosphorylation releases the actin suppression and

Actin-depolymerizing factor (**ADF**)/**coffilin** are an evolutionarily conserved F-actinbinding protein, whose function is essential for cortical actin cytoskeleton. It is well known that the actin-binding ability of ADF/coffilin can be regulated by its phosphorylation and dephosphorylation (Bamburg et al. 1999). This type of regulation of ADF/coffilin has been reported in maturing oocytes of starfish, where active transport of MPF from nucleus to cytoplasm is required for oocyte maturation (Santella et al. 2003), and dividing embryos of *Xenopus*, where cytokinesis involves the function of ADF/coffilin (Abe et al. 1996; Chiu et al. 2010; Tanaka et al. 2005). In the former case, MPF has been identified as a kinase for ADF/coffilin. In the latter case, protein phosphatase Slingshot is involved in Rho-dependent inactivation of ADF/coffilin, thereby promotes the rearrangement of actin cytoskeleton

**ASIP**/**PAR-3** (atypical PKC isotype-specific interacting protein/partitioning defective 3) is a PDZ-domain-containing adaptor protein that has been initially identified as a downstream element of PAR-6 in early embryos of the nematode *C. elegans* (Watts et al. 1996). Further studies have demonstrate the importance of PAR3 as an atypical PKC (aPKC)-interacting protein functioning in establishing asymmetric cell division and polarized cell structures in *C. elegans* and *Drosophila* embryos, and mammalian epithelial cells (Joberty et al. 2000). In *Xenopus* immature oocytes, ASIP/PAR-3 is shown to localize to animal hemisphere in association with aPKC, and upon hormone-induced oocyte maturation, aPKC undergoes kinase activity-dependent re-localization. These results suggest a potential role of ASIP/PAR-3 as a regulator and/or substrate of aPKC (Nakaya et al. 2000). Although phosphorylation of Ser-827 in ASIP/PAR-3 by aPKC has been shown in mammalian somatic cell systems (Hirose et al. 2002), its occurrence in

**Astrin** is a spindle-associated non-motor protein that regulates mitotic cell cycle progression. In the meiosis of mouse oocytes, where centrioles are missing but multiple microtubule-organizing centers (MTOCs) are present, proper lining and segregation of homologous chromosomes and sister chromatids require the precise regulation of MTOCs by centrosomal protein kinases such as Aurora kinase and PLK1. It has been shown that inhibition of Astrin function by RNAi-mediated knockdown or overexpression of a coiledcoil domain of Astrin results in a defect in spindle disorganization, chromosome misalignment and meiosis progression arrest (Yuan et al. 2009). As Astrin localizes to the spindle apparatus, it is suggested that Astrin is a substrate of Aurora/PLK1. In support with this idea, site-directed mutation of Thr-24, Ser-66 or Ser-447, potential PLK1

cortical granule exocytosis occurs (Eliyahu et al. 2005).

**2.2 ADF/coffilin**

essential for cytokinesis.

oocyte/egg system is not yet demonstrated.

**2.3 ASIP/PAR-3**

**2.4 Astrin**

**Bad** is a member of BH3 (Bcl-2 homology 3) family proteins, the other members of which include Bax, Bak, Bik, Bid and Hrk. While Bcl-2, a firstly identified BH3 and other BH domain (BH1 and BH2)-containing protein, and its relative proteins (e.g. Bcl-xL) act as antiapoptosis components, Bad and other BH3-only proteins participate in pro-apoptotic cellular functions (e.g. activation of caspases) (Danial 2008; Lutz 2000). Most of these antiapoptotic or pro-apoptotic proteins localize to mitochondrial outer membranes and function as a sensor of intracellular damage as well as a trigger of mitochondrial death/survival pathway. Several species ranging from nematode, *Drosophila* and sea invertebrates to vertebrates including mammals undergo germline or ovarian/postovulatory oocyte apoptosis in an age-dependent or -independent manner (Buszczak and Cooley 2000; Chiba 2004; Morita and Tilly 1999). In particular, Bad has recently been identified as a factor for phospho-dependent mechanism of egg apoptosis in *Xenopus* (Du Pasquier et al. 2011). Bad in ovarian oocytes at the first meiotic propahse is negatively regulated by inhibitory phosphorylation on Ser-112 and Ser-136 by unknown mechanism (maybe PKA phosphorylation). Upon oocyte maturation, Bad becomes further phosphorylated on Ser-128 in a CDK- and JNK-dependent manner. The Ser-128 phosphorylation, if it exceeds the extent of those of Ser-112/Ser-136 phosphorylations during a long period of oocyte maturation in the absence of fertilizing sperm, will allow Bad to trigger a mitochondrial apoptotic pathway involving cytochrome c release and caspase activation. Whether normal process of oocyte maturation and fertilization involves anti-apoptotic mechanism is not known.

## **2.6 Brain-derived neurotrophic factor (BDNF)**

**BDNF** is a member of neurotropic family of growth factors that include nerve growth factor (NGF). Its cellular functions are exerted by cell surface receptors such as TrkB, a tyrosine kinase/receptor, and p75 low-affinity NGF receptor (Chao and Hempstead 1995). In mammals including human, ovarian BDNF has been implicated in oogenesis, oocyte maturation, and pre-implantation embryogenesis (Kawamura et al. 2005; Zhang et al. 2010). In vitro maturation of mouse oocytes in the presence of cumulus cells is accompanied by BDNF-dependent activation of Akt/PKB and MAPK and its maintenance has been demonstrated (Zhang et al. 2010). Pharmacological experiments suggest that the Akt/PKB activation involves TrkB function (TrkB-PI3K-PIP3 pathway), while the MAPK does not.

### **2.7 Bub1/BubR1**

**Bub1** and **BubR1** (Mad3 in yeast, worms and plants) are multidomain-containing proteinserine/threonine kinases that have been characterized as components of the mitotic checkpoint of spindle assembly (Bolanos-Garcia and Blundell 2011). In mouse oocytes, BubR1 is shown to act as a spindle assembly checkpoint protein in the first meiotic arrest (Homer et al. 2009; Jones and Holt 2010; Schwab et al. 2001; Wei et al. 2010). In maturing *Xenopus* oocytes, Bub1 is activated by MAPK-dependent p90Rsk phosphorylation, and is suggested to be involved in spindle assembly checkpoint and, in collaboration with

Phospho-Signaling at Oocyte Maturation and Fertilization:

**2.11 Cdc25 phosphatase (Cdc25A/B/C)**

embryonic cell cycle regulation (Kim et al. 1999b).

**2.12 Cdh1/Cort/Fzy**

**2.13 Cohesin/SCC1/Rec-8**

Set Up for Embryogenesis and Beyond Part II. Kinase Regulators and Substrates 503

and/or Bub1/BubR1 kinases, key regulators of spindle checkpoint, and it is involved in the maintenance of cytostatic factor activity that involves the inactivation of APC. Analyses using cell-free extracts prepared from unfertilized *Xenopus* eggs demonstrate that the phosphorylated form of Cdc20 is a target of calcineurin, whose phosphatase activity is

**Cdc25** is a protein-tyrosine phosphatase that has been originally identified and characterized as a yeast cell cycle regulator (Fleig and Gould 1991). A major target of this phosphatase is the Cdc2 protein-serine/threonine kinase, its cyclin-associated form of which functions as MPF. Before oocyte maturation in vertebrates, the activity of Cdc2 protein is down-regulated by the absence of cyclin and by phosphorylation by Myt1/Wee1 dualspecificity kinases on Thr-14 and Tyr-15 residues. During oocyte maturation, however, both accumulation of newly synthesized cyclin as well as removal of the phosphates from Cdc2 ensures the Cdc2 activation (Karaiskou et al. 1998; Kim et al. 1999b; Oh et al. 2010; Perdiguero and Nebreda 2004; Perdiguero et al. 2003; Pirino et al. 2009; Qian et al. 2001; Rime et al. 1994; Zhang et al. 2008; Zhao et al. 2008). There are several types of Cdc25: e.g. Cdc25A, Cdc25B, and Cdc25C. PKA phosphorylation and activation of Cdc25B has been reported in mammals (Pirino et al. 2009). In *Xenopus*, Cdc25C is up-regulated by Plx1 mediated phosphorylation on Ser-287 (Qian et al. 2001). Other reports have shown that Xp38/SAPK (Perdiguero et al. 2003) and Greatwall kinase (Zhao et al. 2008) can be responsible for the stimulatory phosphorylation of Cdc25C. Cdc25A has been implicated in

**Cdh1** is an activator of anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that regulates the onset of anaphase during meiotic and mitotic cell cycle (Visintin et al. 1997). Several cell cycle regulators are subjected to Cdh1- and proteasome-dependent degradation, by which APC/C-dependent cell cycle progression through anaphase is triggered. In *Xenopus* egg cell-free extracts, Cdh1-dependent degradation of Aurora A kinase plays an important role in mitotic exit (Littlepage and Ruderman 2002). The Aurora A-Cdh1 interaction requires the phosphorylation of Aurora A on Ser-53 residue, which is a substrate of M-phase-activated kinase(s). On the other hand, APC-independent cellular function involving Cdh1 has also been suggested in *Xenopus* oocyte maturation (Papin et al. 2004). In immature mouse oocytes, where the meiotic cell cycle is paused at the prophase I, Emi1 dependent mechanism of cdh1 inhibition (thereby inhibition of APC/C) functions for the MI arrest (Marangos et al. 2007). In *Drosophila* and *C. elegans*, Cdc20/Cdh1-related protein, Cort and Fzy, respectively, controls the meiotic cell cycle progression in a Cdh1-like manner

**Cohesin** is a chromosome-binding protein that is involved in meiotic and mitotic assembly and segregation of sister chromatids (Heck 1997). In many vertebrate species, cell cycle progression through anaphase involves a proteolytic cleavage of cohesin, as catalyzed by separase and subsequent release of cohesin from the sister chromatids, so that the

(Kitagawa et al. 2002; Marangos et al. 2007; Swan and Schupbach 2007).

transiently activated in response to Ca2+ signals (Mochida and Hunt 2007).

cdk2/cyclin E complex, cytostatic arrest of the meiosis II (Schwab et al. 2001; Tunquist et al. 2002). Precise mechanism of the cytostatic arrest, i.e. inhibition of anaphase-promoting complex, is not known, because a substrate of Bub1 has not yet been identified. In mammals, first meiotic anaphase also seems to be regulated by Bub1-dependent mechanism (McGuinness et al. 2009).

## **2.8 Calcineurin**

**Calcineurin** is a protein serine/threonine-specific phosphatase that can be up-regulated by the binding of Ca2+/calmodulin (Pallen and Wang 1985), another target of which is CaMKII. In *Xenopus* eggs and cell-free egg extracts, Ca2+-dependent exit of meiosis II involves transient activation of calcineurin. When the activation of calcineurin is blocked, inactivation of MPF by means of cyclin degradation does not occur and sperm nuclei remains condensed. In addition, cortical contraction of the pigmented granules in the animal hemisphere is also blocked. On the other hand, if the activity of calcineurin is artificially kept up-regulated for a prolonged period, growth of sperm aster is inhibited and fusion of the female and male pronuclei is also inhibited. It has been shown that calcineurin dephosphorylates Cdc20, a key regulator of the anaphase-promoting factor that is a substrate of MAPK (Mochida and Hunt 2007; Nishiyama et al. 2007). These results highlight a requirement of calcineurin for Ca2+-dependent inactivation of cytostatic factor and for the onset of the mitotic cell cycle in the early embryos.

## **2.9 Caspase 2**

**Caspase 2** is a member of caspase family, which regulates and/or triggers the apoptotic cell death in response to a wide variety of extracellular and intracellular signals. It has been shown that in caspase 2-deficient mice, excess number of ovarian oocytes is a major cause, suggesting that caspase 2 is involved in ovarian oocyte apoptosis. Oocytes deficient in caspase 2 expression also exhibit a marked resistance to cell death induced by chemicals (Bergeron et al. 1998; Morita and Tilly 1999). Further insight into the roles of caspase 2 in the control of oocyte survival has been demonstrated by the studies with use of cell-free extracts prepared form *Xenopus* eggs. In this system, glucose-6-phosphate has been identified as an important component to drive continual operation of the pentose phosphate pathway that prolongs cell survival. In addition, NADPH generation by this pathway is critical for promoting CaMKII-dependent inhibitory phosphorylation of caspase 2 (Nutt et al. 2005). As CaMKII is known as a crucial component that inactivates CSF activity in frog and mammals, it is intriguing whether the CaMKII-caspase 2 axis also functions at fertilization.

#### **2.10 Cdc20/Fizzy**

**Cdc20** is an activator of anaphase-promoting complex (APC) that directs the onset and progression of the meiotic and mitotic cell cycle (Chung and Chen 2003; Rudner and Murray 2000; Shteinberg et al. 1999; Tang et al. 2004; Weinstein 1997). In *Drosophila*, Cdc20-related gene Fizzy serves a similar function (Dawson et al. 1993; Pesin and Orr-Weaver 2008). The activity of Cdc20 is negatively regulated by phosphorylation on its serine and threonine residues: in case of *Xenopus* Cdc20, Ser-50, Thr-64, Thr-68 and Thr-79. In *Xenopus* maturing oocytes, phosphorylation of Cdc20 is catalyzed by MAPK, a component of cytostatic factor, and/or Bub1/BubR1 kinases, key regulators of spindle checkpoint, and it is involved in the maintenance of cytostatic factor activity that involves the inactivation of APC. Analyses using cell-free extracts prepared from unfertilized *Xenopus* eggs demonstrate that the phosphorylated form of Cdc20 is a target of calcineurin, whose phosphatase activity is transiently activated in response to Ca2+ signals (Mochida and Hunt 2007).

## **2.11 Cdc25 phosphatase (Cdc25A/B/C)**

502 Embryogenesis

cdk2/cyclin E complex, cytostatic arrest of the meiosis II (Schwab et al. 2001; Tunquist et al. 2002). Precise mechanism of the cytostatic arrest, i.e. inhibition of anaphase-promoting complex, is not known, because a substrate of Bub1 has not yet been identified. In mammals, first meiotic anaphase also seems to be regulated by Bub1-dependent mechanism

**Calcineurin** is a protein serine/threonine-specific phosphatase that can be up-regulated by the binding of Ca2+/calmodulin (Pallen and Wang 1985), another target of which is CaMKII. In *Xenopus* eggs and cell-free egg extracts, Ca2+-dependent exit of meiosis II involves transient activation of calcineurin. When the activation of calcineurin is blocked, inactivation of MPF by means of cyclin degradation does not occur and sperm nuclei remains condensed. In addition, cortical contraction of the pigmented granules in the animal hemisphere is also blocked. On the other hand, if the activity of calcineurin is artificially kept up-regulated for a prolonged period, growth of sperm aster is inhibited and fusion of the female and male pronuclei is also inhibited. It has been shown that calcineurin dephosphorylates Cdc20, a key regulator of the anaphase-promoting factor that is a substrate of MAPK (Mochida and Hunt 2007; Nishiyama et al. 2007). These results highlight a requirement of calcineurin for Ca2+-dependent inactivation of cytostatic factor and for the

**Caspase 2** is a member of caspase family, which regulates and/or triggers the apoptotic cell death in response to a wide variety of extracellular and intracellular signals. It has been shown that in caspase 2-deficient mice, excess number of ovarian oocytes is a major cause, suggesting that caspase 2 is involved in ovarian oocyte apoptosis. Oocytes deficient in caspase 2 expression also exhibit a marked resistance to cell death induced by chemicals (Bergeron et al. 1998; Morita and Tilly 1999). Further insight into the roles of caspase 2 in the control of oocyte survival has been demonstrated by the studies with use of cell-free extracts prepared form *Xenopus* eggs. In this system, glucose-6-phosphate has been identified as an important component to drive continual operation of the pentose phosphate pathway that prolongs cell survival. In addition, NADPH generation by this pathway is critical for promoting CaMKII-dependent inhibitory phosphorylation of caspase 2 (Nutt et al. 2005). As CaMKII is known as a crucial component that inactivates CSF activity in frog and mammals,

it is intriguing whether the CaMKII-caspase 2 axis also functions at fertilization.

**Cdc20** is an activator of anaphase-promoting complex (APC) that directs the onset and progression of the meiotic and mitotic cell cycle (Chung and Chen 2003; Rudner and Murray 2000; Shteinberg et al. 1999; Tang et al. 2004; Weinstein 1997). In *Drosophila*, Cdc20-related gene Fizzy serves a similar function (Dawson et al. 1993; Pesin and Orr-Weaver 2008). The activity of Cdc20 is negatively regulated by phosphorylation on its serine and threonine residues: in case of *Xenopus* Cdc20, Ser-50, Thr-64, Thr-68 and Thr-79. In *Xenopus* maturing oocytes, phosphorylation of Cdc20 is catalyzed by MAPK, a component of cytostatic factor,

(McGuinness et al. 2009).

onset of the mitotic cell cycle in the early embryos.

**2.8 Calcineurin**

**2.9 Caspase 2**

**2.10 Cdc20/Fizzy**

**Cdc25** is a protein-tyrosine phosphatase that has been originally identified and characterized as a yeast cell cycle regulator (Fleig and Gould 1991). A major target of this phosphatase is the Cdc2 protein-serine/threonine kinase, its cyclin-associated form of which functions as MPF. Before oocyte maturation in vertebrates, the activity of Cdc2 protein is down-regulated by the absence of cyclin and by phosphorylation by Myt1/Wee1 dualspecificity kinases on Thr-14 and Tyr-15 residues. During oocyte maturation, however, both accumulation of newly synthesized cyclin as well as removal of the phosphates from Cdc2 ensures the Cdc2 activation (Karaiskou et al. 1998; Kim et al. 1999b; Oh et al. 2010; Perdiguero and Nebreda 2004; Perdiguero et al. 2003; Pirino et al. 2009; Qian et al. 2001; Rime et al. 1994; Zhang et al. 2008; Zhao et al. 2008). There are several types of Cdc25: e.g. Cdc25A, Cdc25B, and Cdc25C. PKA phosphorylation and activation of Cdc25B has been reported in mammals (Pirino et al. 2009). In *Xenopus*, Cdc25C is up-regulated by Plx1 mediated phosphorylation on Ser-287 (Qian et al. 2001). Other reports have shown that Xp38/SAPK (Perdiguero et al. 2003) and Greatwall kinase (Zhao et al. 2008) can be responsible for the stimulatory phosphorylation of Cdc25C. Cdc25A has been implicated in embryonic cell cycle regulation (Kim et al. 1999b).

## **2.12 Cdh1/Cort/Fzy**

**Cdh1** is an activator of anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that regulates the onset of anaphase during meiotic and mitotic cell cycle (Visintin et al. 1997). Several cell cycle regulators are subjected to Cdh1- and proteasome-dependent degradation, by which APC/C-dependent cell cycle progression through anaphase is triggered. In *Xenopus* egg cell-free extracts, Cdh1-dependent degradation of Aurora A kinase plays an important role in mitotic exit (Littlepage and Ruderman 2002). The Aurora A-Cdh1 interaction requires the phosphorylation of Aurora A on Ser-53 residue, which is a substrate of M-phase-activated kinase(s). On the other hand, APC-independent cellular function involving Cdh1 has also been suggested in *Xenopus* oocyte maturation (Papin et al. 2004). In immature mouse oocytes, where the meiotic cell cycle is paused at the prophase I, Emi1 dependent mechanism of cdh1 inhibition (thereby inhibition of APC/C) functions for the MI arrest (Marangos et al. 2007). In *Drosophila* and *C. elegans*, Cdc20/Cdh1-related protein, Cort and Fzy, respectively, controls the meiotic cell cycle progression in a Cdh1-like manner (Kitagawa et al. 2002; Marangos et al. 2007; Swan and Schupbach 2007).

#### **2.13 Cohesin/SCC1/Rec-8**

**Cohesin** is a chromosome-binding protein that is involved in meiotic and mitotic assembly and segregation of sister chromatids (Heck 1997). In many vertebrate species, cell cycle progression through anaphase involves a proteolytic cleavage of cohesin, as catalyzed by separase and subsequent release of cohesin from the sister chromatids, so that the

Phospho-Signaling at Oocyte Maturation and Fertilization:

**2.17 Initiation factor 4E-binding protein (4E-BP)**

maturing oocytes of starfish (Lapasset et al. 2008).

**2.18 EGG-3/4/5**

Parry et al. 2009).

subsequent PKC activation.

Set Up for Embryogenesis and Beyond Part II. Kinase Regulators and Substrates 505

serine/threonine kinase (Nishizuka 1984; Nishizuka 1986). DG also acts as a substrate of DG kinase that produces phosphatidic acid or PA, which has pleiotropic cellular functions. In *Xenopus* eggs, fertilization promotes a rapid increase in intracellular DG concentration, a large part of which seems to be due to phospholipase D (PLD)-mediated cleavage of phosphatidylcholine (PC) (but not PIP2). In support of this, choline, another product of PC hydrolysis by PLD, is also accumulating in a similar time course of fertilization. Whether DG is involved in the activation of egg PKC remains to be clarified (Stith et al. 1997). Production of DG has also been examined in mouse eggs (Stith et al. 1997; Yu et al. 2008). In this species, sperm-derived PLC seems to be mainly responsible for DG production and

**4E-BP** is a binding protein for eukaryotic initiation factor 4E (eIF4E), an mRNA cap-binding protein that facilitates the initiation of protein synthesis in association with eIF4F. The interaction between 4E-BP and eIF4E depends on the phosphorylation state of 4E-BP: hypophosphorylated form of 4E-BP has an ability to bind to and inhibit eIF4E, whereas the phosphorylated form of 4E-BP releases eIF4E so that eIF4E-eIF4F complex is formed and promotes active translation of mRNA (Lasko 2003). In sea urchin eggs, fertilization is accompanied by a rapid burst of protein synthesis. It has been shown that fertilization also promotes a rapid decrease in 4E-BP as well as an increase in phosphorylated form of 4E-BP (Cormier et al. 2001). Two-dimensional electrophoresis demonstrated that 4E-BP is phosphorylated on multiple sites after fertilization. In mitotic sea urchin embryos, further decrease in 4E-BP expression has been demonstrated and it is mediated by a rapamycinsensitive mechanism of proteolysis of 4E-BP (Salaun et al. 2003), suggesting that mTOR (mammalian target of rapamycin)-like kinase is involved in the phosphorylation of 4E-BP. A rapamycin-sensitive mechanism of global protein synthesis involving 4E-BP regulation (but not translation of some proteins such as cyclin B and Mos, whose translational control involves the phosphorylation of CPEB phosphorylation) has also been demonstrated in

*C. elegans* **EGG-3** is a member of protein-tyrosine phosphatase-like (PTPL) family, whose mutant egg undergoes fertilization normally but has a defect in polarized dispersal of Factin, formation of chitin eggshell, and production of polar bodies (Maruyama et al. 2007). Although enzymatic substrate for EGG-3 has not yet been demonstrated (PTPL proteins are supposed to be pseudo-phosphatase), its functional interaction with CHS-1, which is required for deposition of egg shell, plays a role for proper distribution of MBK-2 kinase that regulates degradation of maternal proteins and egg-to-embryo transition (Nishi and Lin 2005; Qu et al. 2006; Qu et al. 2007; Stitzel et al. 2007; Stitzel et al. 2006). Other members of PTPL family such as EGG-4 and EGG-5 have also been characterized as components of meiotic cell cycle progression and egg-to-embryo transition. These two EGG proteins have no phosphatase activity, however, interact with YTY motif of MBK-2 kinase, which is autophosphorylated in the active kinase, and inhibit the kinase activity (Cheng et al. 2009;

chromosomal segregation occurs. In *Xenopus*, however, proteolysis-independent release of cohesin from sister chromatids is working and it involves polo-like kinase phosphorylation of cohesin (Sumara et al. 2002). A similar phospho-dependent release of chromosome cohesion has been demonstrated in *C. elegans*, where the AIR-2 kinase (Aurora B kinase in this species) phosphorylation of the nematode cohesion Rec-8 (Rogers et al. 2002).

#### **2.14 Crk adaptor protein (Crk/CRKL)**

**Crk** is an SH2/SH3-containing adaptor protein that has been originally identified as an oncogene product (viral Crk or v-Crk) of avian sarcoma virus CT10 (Feller et al. 1994; Mayer et al. 1988; Mayer and Hanafusa 1990). Its SH2 domain-dependent phosphotyrosine-binding property and SH3 domain-dependent binding to proline-rich sequences in other molecules are required for malignant cell transformation. Three cellular homologues of v-Crk have been found in mammals: c-Crk I, c-Crk II, and c-Crk-like (CRKL). These cellular Crk family proteins have been identified as a major substrate of Bcr-Abl tyrosine kinase that causes chronic myeloid leukemia (CML) (Feller et al. 1998). Another aspect of Crk function has been demonstrated in the studies of *Xenopus* egg cell-free extract: apoptosis in aged egg extracts is shown to involve interaction between the SH2 domain of Crk and the tyrosinephosphorylated form of Wee1 dual-specificity kinase (Evans et al. 1997; Smith et al. 2000). Further study has demonstrated that the SH3 domain of Crk is important for interacting with the nuclear export factor Crm1, an antagonistic factor for apoptosis in cell-free extract, and that mutually exclusive interaction between Crk and Crm1 or Wee1 in the nucleus regulates the onset of apoptosis.

#### **2.15 Cyclin B**

**Cyclin** is a family of CDK activator proteins, whose first example has been discovered in fertilized sea urchin eggs (Evans et al. 1983) and starfish maturing oocytes (Evans et al. 1983; Standart et al. 1987). Cyclin family consists of several proteins: cyclin A, B, D, E and others, and cyclin B are a component of MPF, another subunit of which is Cdc2/CDK1 serine/threoninespecific protein kinase (Hunt 1989; Maller 1990). In many species, hormone-induced MPF activity in maturing oocytes is generally dependent on *de novo* synthesis and accumulation of cyclin B (and subsequent phospho-dependent regulation of Cdc2/CDK1 by the actions of Wee1/Myt1 kinases and Cdc25 phosphatase is also important) (Gaffre et al. 2011). Fertilization triggers an ubiquitin/proteasome-dependent degradation of cyclin B that causes a rapid decrease of MPF activity (Edgecombe et al. 1991; Huo et al. 2004b; Lapasset et al. 2005; Lapasset et al. 2008; Meijer et al. 1989a; Meijer et al. 1991; Meijer et al. 1989b; Sakamoto et al. 1998). Other cyclins (e.g. cyclin A, D) serve a similar CDK-activating property, but have distinct physiological functions (e.g. G1/S transition, spindle checkpoint) by interacting with a specific CDK member(s) (e.g. CDK2, CDK5).

#### **2.16** *sn***-1,2-diacylglycerol (DG)**

**DG** is one of two hydrolyzed products by phospholipase C of phosphatidylinositol 4,5 bisphosphate, another product of which is inositol 1,4,5-trisphosphate (IP3). DG serve as a second messenger in a variety of extracellular signals such as hormones and neurotransmitters, and is well characterized as a direct activator for PKC, a family of serine/threonine kinase (Nishizuka 1984; Nishizuka 1986). DG also acts as a substrate of DG kinase that produces phosphatidic acid or PA, which has pleiotropic cellular functions. In *Xenopus* eggs, fertilization promotes a rapid increase in intracellular DG concentration, a large part of which seems to be due to phospholipase D (PLD)-mediated cleavage of phosphatidylcholine (PC) (but not PIP2). In support of this, choline, another product of PC hydrolysis by PLD, is also accumulating in a similar time course of fertilization. Whether DG is involved in the activation of egg PKC remains to be clarified (Stith et al. 1997). Production of DG has also been examined in mouse eggs (Stith et al. 1997; Yu et al. 2008). In this species, sperm-derived PLC seems to be mainly responsible for DG production and subsequent PKC activation.

## **2.17 Initiation factor 4E-binding protein (4E-BP)**