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doi: 10.1242/10.1242/jcs.00074
Commentary |
Department of Biological Chemistry, University of Padova, V.le G. Colombo, 3 35121 Padova, Italy and Venetian Institute for Molecular Medicine (VIMM), Via Orus 2, 23129 Padova, Italy
e-mail: lorenzo.pinna{at}unipd.it
 |
Summary |
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 Top Summary IntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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, '' or '), which
are essential for cell viability, and a dimer of two non-catalytic ß
subunits, whose precise function is still poorly understood. Although the
ß subunits deeply affect many properties of CK2, both the isolated
catalytic subunits and the holoenzyme are constitutively active, which is
probably responsible for the oncogenic potential of CK2. Given the structure
of the holoenzyme, the ß subunits could undergo reversible dissociation
under physiological conditions and play a role as anchoring elements and/or as
a docking platform for protein substrates and effectors. These unusual
features are likely to be instrumental in the involvement of CK2 in a number
of key biological functions, notably RNA synthesis, Wnt signaling,
ubiquitination and cell survival.
Key words: Protein kinase, Casein kinase 2, Protein phosphorylation, Signal transduction, Cell regulation, Neoplasia, Apoptosis
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Introduction |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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). After
Litchfield et al. re-evaluated CK2 activity in many extracts from cells
treated with stimuli that had been previously reported to elicit acute
increases in CK2 activity and concluded that "no reproducible increases
in CK2 activity were observed in response to any of these treatments"
(Litchfield, 1994), the paradigm of `regulation equals more activity' in the
case of CK2 started declining. Recent evidence indicates that the opposite
(i.e. regulation equals less activity) applies in one circumstance —
ensuring constitutive transcription of tRNA — when CK2 plays a central
role in all eukaryotes (Ghavidel and
Schultz, 2001). Meanwhile several substantial steps towards
elucidation of the biological roles of CK2 have been made: many new substrates
and partners have been detected; the crystal structures of its catalytic
subunit (Niefind et al.,
1998), of the ß subunit
(Chantalat et al., 1999) and of
the holoenzyme (Niefind et al.,
2001) have been solved, the structural features underlying many of
its unique properties have been unraveled; its importance in neoplasia
(Seldin and Leder, 1995;
Kelliher et al., 1996) and
apoptosis (Guo et al., 2000)
has been demonstrated. Here I provide an updated account of this progress and
speculate about the role of CK2 in some global processes. |
One thousand and one substrates? |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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). The first
endogenous substrates of CK2 came to light in the early 1980s, and in 1990 50
substrates were already known. By 1994 this figure had risen to >100 and by
1997 to 160 (Pinna and Meggio,
1997). To date the repertoire of CK2 substrates includes 307
proteins (F. Meggio and L. A. Pinna, unpublished) and only in relatively few
cases (50 or so) has in vitro phosphorylation not yet been corroborated by
data supporting the occurrence of in vivo phosphorylation as well. This figure
is steadily increasing; eventually it may include a large proportion (one
tenth to one fifth) of the whole eukaryotic phosphoproteome. More telling than
the number, however, is the nature of the proteins phosphorylated by CK2 and
the functions they play in the cell. Not less than sixty of the known
substrates are transcription factors; these, in conjunction with >40
nuclear proteins implicated in gene expression and transcription, a dozen
translational factors and >80 other proteins with various functions in
signalling, make up a substantial majority of substrates implicated in the
cellular signalling network. By comparison, classic metabolic enzymes, such as
glycogen synthase, acetyl CoA carboxylase and ornithine decarboxylase,
represent a minority (a dozen or so) of its substrates. Quite impressive
instead is the list of viral proteins (38) that rely on CK2 for
phosphorylation. As discussed below, this is probably a consequence of the
constitutive activity of CK2, which is exploited by many viruses as a
first-choice phosphorylating agent for proteins essential to their life
cycle.
The fundamental roles of CK2 in signalling, gene expression and other
nuclear processes have been recently highlighted in two analyses of protein
complexes in yeast (Gavin et al.,
2002; Ho et al.,
2002), in which all four CK2 subunits (in yeast a second
regulatory subunit, ß', also exists) were detected in three and
four multiprotein complexes, whereas several other complexes contained two or
three of the CK2 subunits. In the Gavin et al. study two or more CK2 subunits
were found in seven multiprotein complexes (out of the 232 analyzed): four of
these include proteins implicated in transcription, DNA maintenance or
regulation of chromatin structure, one is implicated in RNA metabolism, one is
implicated in protein/RNA transport and one functions in signalling. The
catalytic subunit alone is found in two additional complexes, which
are involved in protein synthesis and turnover and RNA metabolism.
All known CK2 targets share typical phosphoacceptor sites specified by
multiple acidic residues (on average >5) surrounding the phosphoacceptor
residue, which can be serine, threonine or even, in at least one case,
tyrosine. The most important acidic determinant is that at position
n+3 and is found in nearly 90% of the sites analyzed and in all of
the few sites (nine) that have only one acidic determinant. The second most
important acidic determinant is that at position n+1 and is found in
75% of the sites. Whenever the negatively charged determinant is absent at
position n+3, it is invariably present at position n+1 and
vice-versa. Mutational analysis of the CK2 subunit led to the
identification of a network of unique basic residues responsible for the
recognition of the acidic determinants between positions n-1 and
n+4 (Sarno et al.,
1997). Basic residues are extremely rare at any position between
n-1 and n+4 in the CK2 sites, where they behave as negative
determinants. The same applies to the proline residue at position
n+1, which conversely is part of the consensus sequence for CDKs. On
the basis of these data sequences, the following motif can be held as hallmark
of CK2 sites:
 |
where X is any residue except basic residues and X' is any residue except basic or proline residues. The size of the letters is roughly proportional to the frequency of a given residue at that position. Phosphoserine (not indicated) can efficiently replace Glu and Asp at any position; the phosphoacceptor residue is underlined.
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Constitutive activity: the apparent paradox |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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and ', which are encoded by distinct
genes and are very similar to each other except for a C-terminal extension,
present only in the subunit, which includes proline-rich
phosphoacceptor sites whose phosphorylation generates docking sites for
peptidyl-prolyl isomerase Pin1 (Messenger
et al., 2002). In the holoenzyme, two catalytic subunits
(, '' or ')
associate with a dimer of the non-catalytic ß subunit, which does not
share homology with any other regulatory subunit of protein kinases.
Quaternary structure is generally a hallmark of tight regulation. In fact the
PKA holoenzyme, whose heterotetrameric structure is closely reminiscent of
that of CK2, is completely inactive. Activation, promoted by cyclic AMP,
involves the dissociation of the holoenzyme and the release of the free active
catalytic subunits (Fig. 1). By
contrast, the isolated catalytic subunits of cyclin-dependent kinases (CDKs),
which belong to the same group as CK2, are inactive; in this case their
heterodimeric association with a cognate cyclin is a prerequisite for
activation. Full activation, however, also requires the phosphorylation of the
activation loop and can be abolished by phosphorylation of the glycine-rich
loop and by association with a number of low-molecular-weight protein
inhibitors. CDKs therefore must pass four checkpoints before they can become
active. By contrast, CK2 is equipped with at least two independent molecular
devices to keep it constitutively active: unique interactions between the
activation loop and its N-terminal segment (30 residues longer than in CDKs)
that confer constitutive activity upon the isolated catalytic subunit; and
association of the catalytic subunits with the regulatory ß subunits,
which can reactivate intrinsically inactive mutants in which the contacts
between the N-terminal and activation segments have been disrupted
(Sarno et al., 2002). As a
consequence of these redundant mechanisms of activation, both the isolated
subunits and the holoenzyme are endowed with constitutive activity
(Fig. 1).
|
The catalytic activity of the holoenzyme, determined with specific peptide substrates, is somewhat higher than that of the isolated subunits. Notable exceptions however are a limited number of protein substrates that either require the presence of the ß subunit for phosphorylation or conversely are phosphorylated by the catalytic subunits but not by the holoenzyme (e.g. calmodulin). The phosphorylation of the latter group by the holoenzyme is triggered and dramatically enhanced by polybasic peptides (but not polyamines) such as polylysine. It has to be assumed that the effect of the ß subunit on these particular substrates is not mediated by turning on or off catalytic activity, which is constitutively `on', but by specific interactions with the protein substrates, perhaps in combination with polycationic stimulators.
The solution of the crystal structure of the human CK2 holoenzyme
(Niefind et al., 2001) did not
provide a molecular rationale for either the generic increase in catalytic
activity observed in the presence of peptide substrates or the specific effect
of CK2ß on particular protein substrates. In the holoenzyme, a central
ß-ß dimer holds the two catalytic subunits apart. Each subunit makes
contacts with the central core of the proximal ß subunit and with the
C-terminal tail of the distal ß subunit. These contacts do not, however,
alter the overall conformation to an extent that explains why its
catalytic activity is higher than that of the isolated subunit and why it is
no longer dependent on the C-terminal segment. It is also hard to figure out
how the ß subunit could affect accessibility to the catalytic site of
protein substrates whose phosphorylation is either dependent on or prevented
by the ß subunit itself: the N-terminal acidic region of ß, believed
to account for its pseudo-substrate downregulatory potential, is far from the
catalytic sites of both subunits
(Niefind et al., 2001). The
crystal structure might simply provide a fragmentary view of a complex and
dynamic situation in which different conformers of the CK2 holoenzyme exist in
equilibrium: some of these, generated for example by the folding up of the
extended, crab-shaped conformation seen in the crystal or by supramolecular
association (Valero et al.,
1995), might account for functional features that are otherwise
hard to explain. It is also possible that the relatively low resolution of the
structure (3.1 Å) has hampered the detection of subtle yet functionally
relevant structural alterations that could account for changes in activity
(Sarno et al., 2002).
Although the crystal structure has left unsolved a number of mechanistic
issues, it has corroborated the view that the ß subunit, rather than
being a sensu stricto regulatory element, operates as a targeting molecule
and/or a docking platform for binding substrates and effectors and for the
assembly of multimolecular complexes in which CK2 plays a role. Not only does
the shape of the tetramer account for the remarkable tendency of the ß
subunit to interact with a variety of protein `partners' but also, and more
importantly, the nature and the surface of the contacts between the ß and
-subunits (832 A2) make it quite plausible that the
holoenzyme, despite its remarkable stability in vitro, "is a transient
heterocomplex, which is formed and dissociates in vivo for specific functional
and regulatory reasons" (Niefind et
al., 2001). This revives the `wild-card' hypothesis in which
partner proteins serve as switches by variably interacting with CK2 subunits
(Allende and Allende, 1998). In this respect, the ß subunits of CK2 are
more reminiscent of A-kinase-anchoring proteins (AKAPs) than PKA regulatory
subunits (Rs), or, at least, they share some functions of both.
The lack of known physiological effectors makes the development of
cell-permeable, specific inhibitors especially important for probing the
cellular functions of CK2. Some widely used inhibitors are far from being
selective: apigenin, for example, inhibits a dozen protein kinases more
readily than it does CK2 amid a panel of 35 enzymes; and DRB
(dichlororibofuranosyl-benzimidazole) inhibits CK1 almost as effectively as it
does CK2. The most selective inhibitor described so far is
tetrabromobenzotriazole (TBB) (Sarno et
al., 2001), whose crystal structure in complex with CK2
(Battistutta et al., 2001)
could pave the road toward the design of more potent derivatives.
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Les liaisons dangeureuses: the pathogenic potential of CK2 |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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). In general this is due to mutations that result in stable
activation of protein kinases that otherwise are subject to tight control. In
the case of CK2, constitutive activity is an intrinsic property of the enzyme
itself: nevertheless it might, under certain circumstances, cause cell
transformation. In fact, in contrast to other oncogenic protein kinases, there
is no evidence of mutations of CK2 giving rise to tumors. However the levels
of CK2 are elevated in a wide variety of tumors (reviewed by
Guerra and Issinger, 1999;
Tawfic et al., 2001). The
cause-effect correlation between CK2 and neoplastic growth has been
established by experimental models in which inappropriate expression of the
CK2 subunit in lymphocytes of transgenic mice resulted in stochastic
production of lymphomas, and co-expression of the subunit with
proto-oncogenes or its expression under conditions where p53 expression was
altered accelerated development of acute lymphocytic leukemia
(Seldin and Leder, 1995;
Kelliher et al., 1996;
Landesman-Bollag et al., 1998). Also the inclusion of many viral proteins
among CK2 targets strongly suggests a role for CK2 in virally mediated
pathologies, including cancer. Another mechanism by which CK2 can promote
dysregulated growth is inhibition of apoptosis
(Guo et al., 2000). A common
denominator of these observations is that modest alterations in the levels of
CK2 are sufficient to induce dramatic effects on cell fate by
cooperating with other factors. Dysregulation of CK2 expression might
thus impart "an oncogenic potential to the cell such that in cooperation
with certain oncogenes it produces a profound enhancement of the tumor
phenotype" (Tawfic et al.,
2001). |
Why is CK2 essential for cell life? |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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). In
1990, terming CK2 an eminence grise, I wanted to stress the fact that
it acts behind the scenes in such a way that it is indispensable, although it
does not appear to play any prominent role in the hierarchy of cellular
functions. A hurried statement would be that CK2 is of vital importance
because of its pleiotropism: it is in charge of so many tasks that, although
individually none might be indispensable, they cannot be collectively omitted
without fatal consequences. It would be nice, however, to show that behind its
apparent randomness CK2 performs a number of global tasks within the cell and
that there are specific means of regulating its activity at least within a
given process. There are some emerging clues that indicate that this is the
case.
The PolIII connection
The RNA polymerase I and RNA polymerase II complexes were among the first
CK2 substrates to be discovered in the early eighties. It was not until 1996
that the RNA polymerase III (PolIII) machinery was also shown to be a target
of CK2 and to belong to the `élite' whose phosphorylation by CK2
obviously correlates with a change in biological activity. Phosphorylation by
CK2 of the TATA-binding protein (TBP), a subunit of TFIIIB (the core component
of the PolIII transcriptional machinery), promotes a remarkable increase in
PolIII activity, although the step in initiation stimulated by CK2 is not
known. The PolIII model is especially appealing because, being committed to
the synthesis of tRNA and 5SrRNA, PolIII is expected to be constantly active
in living cells except under special circumstances in which transcription has
to be interrupted. Typically these breaks in PolIII activity are imposed by a
signaling pathway generated in response to DNA damage. Gavidel and Schultz
have shown that CK2 normally associates through its ß subunit with the
TBP subunit of TFIIIB and by doing that phosphorylates TBP and sustains PolIII
transcription (Gavidel and Schultz, 2001). Indeed disruption of CK2 causes the
synthesis of tRNA and 5SrRNA to decline by 80-90%. Transcriptional repression
induced by DNA damage is mediated by downregulation of TBP-associated CK2,
which occurs through the release of the catalytic subunits from the complex.
These data support the view that CK2 is the terminal effector in a signaling
pathway that represses PolIII transcription when genome integrity is
compromised and suggest that the molecular mechanism leading to downregulation
of CK2 is the dissociation of the catalytic subunits from the ß-ß
dimer anchored to the complex — an event plausible in the context of the
crystallographic data discussed above. This would imply that changes in
conformation weaken the interactions between the TBP-associated ß-ß
dimer and the catalytic subunits, which would be expelled from the complex.
How this might take place and how the signals from DNA damage sensors are
transduced to TBP-bound CK2 are unknown. In any case, a remarkable merit of
this study is that it highlights a central function of CK2 in which its two
paradoxical properties, constitutive activity and regulation by deactivation,
not only make sense but are instrumental to the whole process.
The Wnt pathway connection
Wnt signalling, initiated by secreted Wnt proteins that bind to members of
the Frizzled receptor family, plays a central role in development and
homeostasis. A key element in the pathway is the level of cytosolic
ß-catenin, which triggers the activation of Wnt responsive genes. Without
Wnt stimulation, ß-catenin is steadily degraded by the proteasome. This
degradation strictly depends upon ß-catenin phosphorylation occurring in
a multiprotein complex by a hierarchical mechanism involving both CK1 and
glycogen synthase kinase 3 (GSK3). This phosphorylation is critical for
binding of ß-catenin to the F-box protein ß-TrCP, which imparts
specificity on the ubiquitination apparatus. Wnt signaling inhibits GSK3 and
prevents the ubiquitination and degradation of ß-catenin, thus inducing
its accumulation in the cytosol and the activation of Wnt responsive genes,
some of which are proto-oncogenes. Dysregulated activation of the Wnt signal
can therefore give rise to tumors, and inhibition of GSK3, a potential target
for diabetes therapy, in principle could cause cancer. A first indication that
CK2 is also implicated in Wnt signalling was provided by Willert et al. who
showed that CK2 associates with and phosphorylates Dsh
(Willert et al., 1997), the
Drosophila homolog of mammalian Dvl, which is a key component of the
regulatory complex in which the GSK3-catalyzed phosphorylation of
ß-catenin is abrogated by Frat-1. More recently Song et al. have shown
that increased proliferation of a mammary epithelial cell line after Wnt1
transfection is accompanied by increased levels of CK2 and
ß-catenin (Song et al.,
2000). They also showed that CK2 forms complexes with
ß-catenin and Dvl, which do not, however, include GSK3. Inhibition of CK2
reduces the level of ß-catenin and blocks proliferation of
Wnt-transfected cells, suggesting that ß-catenin phosphorylated by CK2
escapes ubiquitination and degradation. Consequently when GSK3 is inhibited by
Wnt signalling, phosphorylation of ß-catenin by CK2 would become
predominant, leading to an increased level of ß-catenin available to
activate Wnt-responsive genes. Although the residue(s) of ß-catenin
phosphorylated by CK2 are not known, these are obviously different from those
affected by GSK3. The work of Song et al. thus provides a clue to the
oncogenic potential of CK2 (Song et al.,
2000), inasmuch as ß-catenin is also upregulated in
transgenic tumors induced by CK2.
Note, however, that both ß-catenin and CK2 play more intricate and
apparently controversial roles in the cell than it might appear from this
straightforward model. Under different experimental conditions, ß-catenin
overexpression blocks the cell cycle and induces apoptosis instead of
proliferation (Kim et al.,
2000), and in fibroblasts, CK2 phosphorylates UBC3 and by doing so
activates the F-box of the ubiquitination machinery, ultimately promoting the
degradation of cytosolic ß-catenin
(Semplici et al., 2002). Once
again the pleiotropy of CK2 hampers an unequivocal explanation of its
functions. It is tempting to speculate that in this case the dissociation of
CK2 holoenzyme switches its action from one pathway to another
(Fig. 2). Although
phosphorylation of UBC3 is strongly stimulated in vitro and perhaps entirely
dependent in vivo on the ß-subunit
(Semplici et al., 2002),
phosphorylation of ß-catenin could rely on the catalytic subunit alone.
Two observations are consistent with this possibility: the lack of CK2ß
in immunoprecipitates in which CK2 and ß-catenin are present
together; and the finding that ß-catenin is upregulated in transgenic
tumors transfected with CK2 alone
(Song et al., 2000). Such a
scenario is also consistent with the view that the oncogenic potential of
CK2 is not enhanced but eventually decreased by co-transfection of the
ß-subunit (Li et al.,
1999) and that increased expression of CK2ß results in
increases in total cellular CK2 activity but no changes in cell proliferation
(Vilk et al., 2002). Moreover,
the existence of two pools of CK2, both constitutively active but having
different functions, would account for the redundancy of CK2 activation
mechanisms, ensuring that not only the holoenzyme but also the isolated
catalytic subunits are constitutively active
(Sarno et al., 2002).
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The caspase connection
Ruzzene et al. have recently provided evidence to support the concept that
CK2 counteracts apoptosis by showing that a specific CK2 inhibitor (TBB)
induces apoptosis in Jurkat cells (Ruzzene
et al., 2002). In the course of this study they observed that
inhibition of CK2 promoted the dephosphorylation of the apoptotic protein HS1
and its accelerated degradation by caspases. They also showed that in vitro
CK2-mediated phosphorylation prevents the cleavage of HS1 by caspase 3.
Interestingly HS1 is not the only protein made refractory to caspase cleavage
by CK2 phosphorylation: phosphorylation of Max
(Krippner-Heidenreich et al.,
2001), Bid (Desagher et al.,
2001), connexin 45.6 (Yin et
al., 2001) and probably also presenilin-2
(Walter et al., 1999) by CK2
also downregulates caspase-dependent degradation. Whether the adverse effect
of CK2 on caspase cleavage is site directed (as suggested, in some cases, by
the proximity of the phosphorylated residue to the site of cleavage) or
mediated by conformational changes, is still an open question. Nevertheless
this observation opens a window on a possible general mechanism by which CK2
counteracts apoptosis and provides a unifying theory to explain the
phosphorylation by CK2 of otherwise unrelated sets of proteins.
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Conclusions and perspectives |
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TopSummaryIntroductionOne thousand and one...Constitutive activity: the...Les liaisons dangeureuses: the...Why is CK2 essential...Conclusions and perspectivesReferences |
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Acknowledgments |
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