913.4 Serine/Threonine Protein Phosphatases in Cell Cycle
Control
As aforementioned, mitotic entry is characterised by massive changes in the phos-
phorylation state of both structural as well as regulatory components of the cell cycle
machinery. These changes trigger key cell cycle events such as nuclear envelope
breakdown (NEBD), chromatin condensation and assembly of a bipolar spindle
(Olsen et al. 2010 ; Hegemann et al. 2011 ). These events mediated by multiple serine/
threonine-directed protein kinases are reversed during exit from M-phase by protein
phosphatases. There are three families of serine/threonine (Ser/Thr) phosphatases:
the phosphoprotein phosphatases (PPPs), the metal-dependent protein phosphatases
(PPMs) and the aspartate-based phosphatases FCP/SCP (Shi 2009 ). In this book
chapter, we will focus primarily on the role of protein phosphatases of the PPP type
as their function in cell cycle regulation is best understood. Due to the large discrep-
ancy between the number of known Ser/Thr kinases (~400) and phosphatase cata-
lytic core subunits (~30), it was believed for a long time that phosphatases are rather
unregulated enzymes with low substrate specificity that work like lawnmowers
(trimming phosphates in a relative nonspecific manner from many different proteins)
to reset the cell cycle machinery to the dephosphorylated interphase state (Shi 2009 ;
Ceulemans and Bollen 2004 ). This simplistic view is clearly wrong. In cells, PPPs do
not exist as naked catalytic subunits, but in a complex with regulatory subunits that
mediate substrate specificity, localisation and activity. Thus, there are many different
holoenzymes with specific and distinct functions that share the same catalytic sub-
unit (Shi 2009 ; Janssens et al. 2008 ; Virshup and Shenolikar 2009 ). Within the fam-
ily of PPPs, type 1 (protein phosphatase 1, PP1) and type 2A (PP2A) phosphatases
have been implicated—among other functions in various cellular pathways—in the
dephosphorylation of mitotic regulators (Fernandez et al. 1992 ; Ferrigno et al. 1993 ;
Nelson et al. 1997 ; Wu et al. 2009 ; Mochida et al. 2009 ; Manchado et al. 2010 ;
Schmitz et al. 2010 ; Cundell et al. 2013 ). Here, we will explain briefly what is known
about the mitotic function and regulation of these phosphatases.
3.5 Type 2A Protein Phosphatases (PP2As)
The quest for the phosphatase that removes mitotic phosphorylations identified
PP2A as the major Cdk1 antagonising phosphatase (Ferrigno et al. 1993 ; Mayer-
Jaekel et al. 1994 ). PP2A is ubiquitously expressed in mammalian cells and can
account for ~0.2 % of the total cellular protein content (Ruediger et al. 1991 ). In
cells, PP2A is either present as a dimeric core enzyme or as a trimeric holoenzyme.
The core dimer consists of the catalytic C-subunit (two isoforms: PPP2CA and
PPP2CB) and the scaffold A-subunit (two isoforms: PPP2R1A and PPP2R1B). The
core dimer then associates with a regulatory B-type subunit, which mediates sub-
strate specificity and localisation of the holoenzyme. In the human genome, 15
genes have been identified that encode for B-type subunits belonging to the four
3 Regulation of Cell Division