Vertebrate Development Maternal to Zygotic Control (Advances in Experimental Medicine and Biology)

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3.5.2.1 The Link Between PP2A-B ́56 and the APC/C

Not surprisingly, the cell cycle regulatory machinery harnesses the interplay of
kinases and opposing phosphatases to control the activity of the APC/C as well. An
example is PP2A-B ́56 and its effect on the evolutionarily conserved APC/C inhibi-
tor XErp1/Emi2. As aforementioned, XErp1 inhibits the APC/C, and this activity is
essential to arrest mature oocytes at metaphase of meiosis II (Schmidt et al. 2005 ;
Shoji et al. 2006 ; Rauh et al. 2005 ). Phosphorylation of XErp1 by the mitotic kinase
Cdk1/cyclin-B primes XErp1 for further phosphorylations by Polo-like kinase 1
(Plk1) and casein kinase 1 (CK1), and these phosphorylations result in the destabili-
sation and inhibition of XErp1 (Isoda et al. 2011 ). The inhibitory effect of Cdk1/
cyclin-B on the APC/C inhibitory activity of XErp1 is antagonised by PP2A-B ́56-
mediated dephosphorylation of XErp1. During the MII arrest of Xenopus eggs, this
mechanism maintains the activity of Cdk1/cyclin-B at constant levels despite ongo-
ing synthesis of cyclin-B (Wu et al. 2007 ): once cyclin-B levels reach a critical
upper threshold, XErp1 is inactivated by Cdk1/cyclin-B resulting in APC/C activa-
tion. APC/C activation leads to cyclin-B destruction until PP2A-B ́56 prevails over
Cdk1/cyclin-B resulting in XErp1 dephosphorylation and the re-inhibition of the
APC/C (Isoda et al. 2011 ). In somatic human cells, PP2A-B ́56 has been shown to
be important for fine-tuning the APC/C-mediated destruction of securin. Securin is
an inhibitory chaperone of separase (Ciosk et al. 1998 ), the enzyme that triggers
sister chromatid disjunction at anaphase onset by cleaving the centromeric cohesin
rings that physically tether the chromosomes together. Securin is degraded by the
APC/C once the SAC is satisfied by the correct attachment of all chromosomes to
the mitotic spindle (Cohen-Fix et al. 1996 ). Ca2+/calmodulin-dependent kinase II
(CaMKII) phosphorylation of securin converts it into a better APC/C substrate
(Hellmuth et al. 2014 ). However, a pool of PP2A-B ́56 that is associated with sepa-
rase stabilises separase-bound securin by keeping it dephosphorylated. By ensuring
that the large pool of free securin is degraded before the separase-bound fraction,
this mechanism contributes to the abruptness and fidelity of sister chromatid segre-
gation in anaphase (Hellmuth et al. 2014 ).

PP1

P

Cdc25

P

14-3-3 P

Plx1

14-3-3

Cdc25

P

14-3-3

MAPK

Cdk2

Cdc25

14-3-3

PKA

P

Cdc25P

PP P

Interphase Mitosis

P

PCdc25

PP2A P

B56δ

CDK1

CycB

P

CDK1

CycB

P P

C

CycA

Fig. 3.6 The activity of Cdc25 is controlled by phosphorylation and 14-3-3 binding.
Phosphorylation of Cdc25 at Xenopus Ser-287 (human Ser-216) recruits 14-3-3. Cdk2/cyclin-A
phosphorylation of Cdc25 interferes with 14-3-3 binding. This phosphorylation event is antago-
nised by PP2A-B ́56. PP1 promotes M-phase entry by dephosphorylating Ser-287

3 Regulation of Cell Division