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(The FASEB Journal. 2003;17:349-368.)
© 2003 FASEB

One-thousand-and-one substrates of protein kinase CK2?

FLAVIO MEGGIO and LORENZO A. PINNA1

Dipartimento di Chimica Biologica and Istituto di Neuroscienze del CNR, Università di Padova and Venetian Institute for Molecular Medicine (VIMM), Padova, Italy

1Correspondence: Dipartimento di Chimica Biologica, Università di Padova, Viale G. Colombo 3, 35121 Padova, Italy. E-mail: lorenzo.pinna{at}unipd.it


   ABSTRACT
TOP
 ABSTRACT
BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
CK2 (formerly termed "casein kinase 2") is a ubiquitous, highly pleiotropic and constitutively active Ser/Thr protein kinase whose implication in neoplasia, cell survival, and virus infection is supported by an increasing number of arguments. Here an updated inventory of 307 CK2 protein substrates is presented. More than one-third of these are implicated in gene expression and protein synthesis as being either transcriptional factors (60) or effectors of DNA/RNA structure (50) or translational elements. Also numerous are signaling proteins and proteins of viral origin or essential to virus life cycle. In comparison, only a minority of CK2 targets (a dozen or so) are classical metabolic enzymes. An analysis of 308 sites phosphorylated by CK2 highlights the paramount relevance of negatively charged side chains that are (by far) predominant over any other residues at positions n+3 (the most crucial one), n+1, and n+2. Based on this signature, it is predictable that proteins phosphorylated by CK2 are much more numerous than those identified to date, and it is possible that CK2 alone contributes to the generation of the eukaryotic phosphoproteome more so than any other individual protein kinase. The possibility that CK2 phosphosites play some global role, e.g., by destabilizing {alpha} helices, counteracting caspase cleavage, and generating adhesive motifs, will be discussed.—Meggio, F., Pinna, L. A. One-thousand-and-one substrates of protein kinase CK2?


Key Words: CK2 • casein kinase 2 • phosphoacceptor sites • phosphoproteome


   BACKGROUND
TOP
 ABSTRACT
 BACKGROUND
PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
AS MENTIONED in a recent historical review on the origins of protein phosphorylation (1) , the first protein kinase activity was discovered in 1954 by Burnett and Kennedy (2) (for an amusing recollection, see E. P. Kennedy’s autobiography, ref 3 ). Such an activity was first detected in rat liver using casein as phosphorylatable substrate and later found ubiquitously in a variety of organisms and tissues. Curiously, it was not due to any of the classical protein kinases popular early in the protein phosphorylation era (namely, phosphokinase, PKA, PKG, PKC, etc.) but to two in some way unusual protein kinases, provisionally termed casein kinases or phosvitin kinases, now mostly referred to as CK1 and CK2, whose physiological roles remained enigmatic for a long time (for an historical review, see ref 4 ) and still are incompletely understood. At variance with the majority of protein kinases, which are quiescent unless their activity is triggered in response to specific stimuli and effectors, CK2 is constitutively active and independent of either second messengers or phosphorylation events. Such a lack of "on/off" regulatory mechanism is especially striking in view of the quaternary structure of CK2, reminiscent of that of PKA, with two catalytic subunits ({alpha} and/or {alpha}’) assembled with a dimeric "regulatory" ß subunit that, however, neither switches on nor off catalytic activity monitored with specific peptide substrates. In contrast, as discussed elsewhere (5) , the phosphorylation of a subset of protein substrates is deeply affected by the ß subunit through mechanisms not yet understood that do not imply major changes in catalytic efficiencies or site specificity. Even more paradoxical is the fact that CK2, after having remained for more than two decades a "kinase in search of its substrates," later turned out to be the probably most pleiotropic protein kinase existing in eukaryotic organisms. This, in conjunction with the observation that CK2 is essential to cell viability and appears to be implicated in global processes such as tRNA and rRNA synthesis (6) , apoptosis (7) , and cell survival (8) and transformation (9) , accounts for the increasing popularity of CK2, especially among "outsiders." As summarized in Fig. 1 , the first physiological targets of CK2 were detected in the late 1970s to reach the number of 50 in 1990. This figure rose to ~100 in 1994 and to 160 in 1997. Although many structural and functional properties of CK2 are dealt with in other reviews and commentaries (e.g., refs 5 , 8 , 11 , 13 14 15 16 ), this review article focuses on proteins that are phosphorylated by CK2. The updated repertoire of CK2 substrates presented here includes 307 proteins; this number is steadily increasing day after day, and from the analysis of potential phosphoacceptor sites it can be predicted that proteins phosphorylated by CK2 make up a substantial proportion of the "phosphoproteome" and that CK2 dependent phosphorylation may play some general functions within the cell.



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  		Figure 1. Time course of CK2 substrates detection. Data drawn from refs 10 11 12 13 and present paper.


   PROTEINS PHOSPHORYLATED BY CK2: AN UPDATED REPERTOIRE
TOP
 ABSTRACT
 BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
To the best of our knowledge, there are at least 307 proteins whose phosphorylation by CK2 has been reported in the literature; but this is likely to be an underestimate since several proteins may have escaped our search. The proteins are listed alphabetically in Table 1 together with a short description of their function, if known, and the pertinent reference(s). In the majority of cases, the actual implication of CK2 in the in vivo phosphorylation of these proteins was corroborated by the observation that the same residue(s) affected in vitro by CK2 are found phosphorylated in native proteins isolated from living cells. In many instances the physiological implication of CK2 is also supported by pharmacological and/or genetic criteria. For a detailed analysis of the individual situations, we suggest the reader consult the papers quoted in Table 1 and references therein. In only 64 proteins (denoted in Table 1 by italics) has phosphorylation by CK2 been demonstrated in vitro, whereas its in vivo occurrence is still a mere speculation. Sometimes, however, coincidental arguments are available based on analogy with physiological targets, favorable kinetic parameters, and conservation of optimal consensus sequence(s) that support the possible implication of CK2 in the phosphorylation of these proteins also in vivo.


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  		Table 1. Repertoire of proteins phosphorylated by CK2a

More telling than their huge number perhaps is the nature of the proteins listed in Table 1 . As summarized in Table 2 , there are 60 transcriptional factors among them, and 50 proteins affecting the structure of DNA/RNA and/or implicated in RNA synthesis and translation, highlighting altogether the paramount importance CK2 must have in gene expression. Also striking is the number of signaling proteins, which, with the exclusion of transcriptional ones, are more than 80, including 11 calcium binding proteins, 10 protein kinases, and 8 protein phosphatases. Finally, the presence of almost 40 viral proteins corroborates the view that by virtue of its constitutive activity, CK2 has been adopted by viruses as a phosphorylating agent of proteins essential to their life cycle and could therefore represent an enticing target for antiviral drugs. By comparison, metabolic enzymes (9 altogether) represent only a small tribe amid the population of CK2 substrates. At variance with PKA and other second messenger-dependent kinases, CK2 does not drastically affect the catalytic properties of these enzymes, consistent with its main implication in basal functions rather than in acute responses to transient stimuli. Pertinent to this may be the presence among CK2 targets of some proteins that play global functions within the cell, like calmodulin, RNA polymerases, topoisomerases I and II, the oncosuppressor protein p53, and a series of initiation and elongation factors. Consistent with this scenario, a recent systematic study of protein–protein interactions in yeast (181) has disclosed the participation of two or more CK2 subunits to seven protein complexes, four of which are implicated in transcription/DNA maintenance/chromatin structure, one in RNA metabolism, one in protein/RNA transport, and one in signaling.


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  		Table 2. Grouping of CK2 protein substrates according to functiona


   THE STIGMATA OF CK2 PHOSPHOACCEPTOR SITES
TOP
 ABSTRACT
 BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
In 175 of the protein substrates listed in Table 1 , the sites affected by CK2 have been identified; since in many proteins the residues phosphorylated were more than one, we know the structure of 308 sites phosphorylated by CK2 (Table 3 ). This is probably the largest repertoire of sites phosphorylated by an individual kinase available to date. A cursory analysis reveals how reliable were predictions based on model peptide substrates derived from the first CK2 sites identified more than two decades ago, when only very few proteins phosphorylated by CK2 were known. Those pioneer studies showed that CK2 phosphorylation is specified by multiple acidic residues located mostly downstream from the phosphorylatable amino acid (serine being preferred over threonine), the one at position n+3 playing the most crucial function (205 , 206) . They also disclosed the negative role exerted by basic residues at any position close to Ser/Thr and of a prolyl residue at position n+1 (207) , where it is instead absolutely needed to create the consensus sequence for different classes of proline-directed kinases. All the sites listed in Table 3 conform to these rules, with only very few and partial exceptions. The average number of negatively charged side chains (either Glu or Asp or phosphorylated residues) surrounding the phosphorylated amino acid (which is serine in 265 sites, threonine in 42 cases and tyrosine in just one case) is 5.2. In only nine sites (<3%) is just one acidic determinant present (Fig. 2A ), and in these cases it is invariably located at the crucial n+3 position, thus fulfilling the minimum consensus S-x-x-E/D. The importance of this position is highlighted by the histograms of Fig. 2 B showing that although acidic residues predominate at all positions between n-4 and n+7, they reach a peak approaching 90% at position n+3. The second most important position is n+1, where an acidic residue is found in 75% of the sites. Significantly, every time the acidic determinant is lacking at n+1 it is found at n+3, and vice versa (Fig. 2C, D ). Other important information that can be drawn from Fig. 3 B is that basic residues are very rare at CK2 sites and tend to disappear, especially at positions n+1, n+2, and n+3, i.e., where the frequency of acidic residues is higher. The great majority of the 175 protein substrates whose phosphorylated sites are listed in Table 3 belong to mammals (100 are human, 19 belong to rabbit, mouse, or bovine). In all these cases, the CK2 phosphorylation sites are conserved across the mammalian species considered.


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  		Table 3. Repertoire of phosphoacceptor sites phosphorylated by CK2



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  		Figure 2. Frequency of negatively charged side chains at CK2 phosphoacceptor sites. A) Number of acidic and/or phosphorylated residues present at positions between n-4 and n+7 in all the sites listed in Table 3 is plotted against the number of sites expressed as percent of total. B) The frequency (%) of acidic and phosphorylated (solid bars), basic (empty bars), and hydrophobic residues (gray bars) found at the indicated positions relative to all the phospho residues listed in Table 3 is shown. C, D) Same analysis as in panel B has been applied only to sites lacking the acidic determinant at position n+1 (77 sites) and n+3 (37 sites), respectively. C, D) Only acidic residues are considered.



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  		Figure 3. Frequency of individual amino acids within CK2 phosphoacceptor sites. The relative frequency (%) of amino acids found at positions between n-4 and n+7 in all the sites listed in Table 3 is shown. In each abscissa, individual amino acids are alphabetically listed after the one-letter code abbreviation.

A more detailed analysis of the data sequences of Table 3 is presented in Fig. 3 showing the frequency of individual amino acids at positions spanning between n-4 and n+7. It can be seen that glutamic and aspartic acids predominate over any other individual amino acid at all positions, although it is only at positions n+3, n+1,and, to a lesser extent, n+2 where acidic residues (including phosphorylated ones) appear to be critical, occurring with a frequency higher than that of all the other residues collectively taken. These data agree with the optimal sequence provided by an oriented library approach (208) (EDEESEDEE), although the relative frequency of Glu vs. Asp is slightly different. Note, however, that the library approach cannot take into account phosphorylated residues that are conversely found in several natural sites. This includes CK2 into that class of protein kinases whose targeting can be primed by another protein kinase (209) , and accounts for the occurrence of multiphosphorylated sites among putative targets of CK2 (see also below, Table 4 ). A comparison between 500 top proteins selected as CK2 substrates by the Scansite prediction program (http://scansite.mit.edu) and the actual protein substrates listed in Table 1 highlights the potentials and limits of the oriented peptide library approach the Scansite program is based upon. Although the virtual optimal sequence of the library reflects quite faithfully the overall picture emerging from our analysis (Fig. 3) , the majority of proteins listed in Table 1 (253 of 307) are not found in the 500 top list selected by Scansite. This is clearly due to the phenomenon of the "expanded consensus sequence" (210) , as the oriented peptide library approach tends to select the specificity determinants of a given kinase at positions where they are not really required. As already pointed out (210) , this leads the Scansite program to select as first choice PKA substrates proteins with clusters of many consecutive arginines on the amino-terminal side of serine, whereas in most physiological substrates of PKA these are just two at positions n-2 and n-3. Likewise, the first choice substrates of CK2 appear to be those where the target residue is embedded between two entirely acidic sequences, a feature found only in relatively few CK2 targets, many of which are readily phosphorylated, although they include just 2 or 3 acidic residues at the most critical positions, notably n+3, n+1 and n+2 (see Fig. 20A and Table 3 ). The score of these latter sites is far away from the optimal score provided by the library and these are not considered by the Scansite analysis with due priority.


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  		Table 4. Putative protein kinases implicated in the generation of the phosphorylated peptide sequences identified by Ficarro et al. (214) in yeast proteinsa

Mutational studies have shown that the tendency of CK2 to interact with negatively charged side chains at positions from n-1 to n+4 is determined by unique basic residues that in CK2 are present at the end of the activation loop, in the glycine rich loop, and at the beginning of helix-C, respectively (211) . This would imply that typical peptide substrate will bind across the catalytic cleft, bridging between the lower and upper lobes of the kinase. It also accounts for the adverse effect of positively charged side chains that are consequently almost completely absent in CK2 sites. The architecture of the active site and the position of the basic residues involved in peptide substrate recognition are not significantly altered by association with the ß subunit (212) . This accounts for the observation that, although the ß subunit may have profound effects on the targeting of some protein substrates, it does not significantly alter the site specificity determined using peptide substrates (e.g., ref 213 ).

Based on the common denominators outlined above (multiple negatively charged side chains downstream from Ser/Thr with special reference to the n+3 position, absence of positively charged residues nearby and of proline at n+1), it is possible to make reliable predictions about potential CK2 sites in proteins whose phosphorylation has not been yet reported and about the implication of CK2 in the generation of phosphoproteins whenever the responsible kinase is unknown. Interesting hints are provided by recent studies on the yeast proteome. In one (181) , 24 proteins have been found to be associated with protein complexes containing one or both the catalytic subunits of CK2: with one exception, these proteins all include one or more potential phosphorylation sites for CK2 in their sequence, although none had been previously reported to be a CK2 substrate. It is tempting to hypothesize that these proteins, given their interaction with CK2, will be also phosphorylated by this kinase. This would also mean that the list of known substrates displayed in Table 1 , despite its crowdedness, represents just the tip of an iceberg. The same conclusion is supported by the outcome of a recent analysis of the phosphoproteome of Saccharomyces cerevisiae (214) leading to the identification of 216 phosphorylated sites, the majority of which include more than one phospho residue probably due to the methodological approach, expected to increase the yield of multiply phosphorylated peptides. As summarized in Table 4 , 72 phospho residues (22.5%) display the specific hallmarks of CK2 phosphoacceptor motifs; the other 40, characterized by the motif pS/pT-x-x-pS/pT, can be considered either CK2 or CK1 potential sites depending on which the priming phospho residue is. Again, only in sporadic instances had these proteins been earlier reported to be phosphorylated by CK2, corroborating the view that the majority of CK2 substrates are still unknown and that CK2 together with few other protein kinases (notably proline directed kinases, GSK3 and CK1, see Table 4 ), primarily contributes to the generation of the eukaryotic phosphoproteome. It has to be assumed that the consensus sequences of protein kinases, with special reference to Ser/Thr specific ones, represent a necessary condition for phosphorylation; actual targeting of the individual protein substrates bearing the consensus will depend on additional features, notably recruitment to definite subcellular compartments and formation of supramolecular complexes. This also applies to CK2, with special reference to its nuclear translocation (215) and targeting to specific nuclear compartments, where many of its substrates are located (see Table 1 ) and where CK2 recruitment has been correlated with resistance to apoptosis (7) .


   DO CK2 PHOSPHOACCEPTOR SITES PLAY GENERAL FUNCTIONS?
TOP
 ABSTRACT
 BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
The unique features of the sites phosphorylated by CK2 in conjunction with their variability within the overall high conservation of the acidic character suggest that they may serve different general functions in addition to the obvious one of conferring susceptibility to phosphorylation by CK2. Of special interest is the observation of Zetina (216) , who, reviewing recurrent motifs at {alpha}-helices in naturally unfolded proteins, pointed out their striking similarity to the consensus sequences specifically phosphorylated by CK2. Since transition between folded and unfolded is instrumental to the functionality of these proteins, this observation suggests that phosphorylation by CK2 could stabilize helix unfolding. Most of the motifs listed in ref 216 fulfill the CK2 consensus; in 6 cases the proteins are listed in Table 1 among the known substrates of CK2. More important, in the case of stathmin (217) , calmodulin, and HIV Rev protein (Marin et al., unpublished results), the formal proof has been reached that phosphorylation of CK2 sites do act as helix breaker. What makes the connection between CK2 and protein unfolding an appealing field of investigation is the working hypothesis that CK2 might operate at a check point where folded proteins become unfolded and thereafter susceptible to aggregations that are highly toxic to cells (218) . Pertinent to this could also be the presence among CK2 substrates of proteins implicated in neurodegenerative diseases, notably {alpha}-synuclein, ß-amyloid precursor protein, the prion protein, and MAP-associated tau protein (see Table 1 ), whose pathological potential correlates with the ability to form insoluble aggregates.

Another intriguing possibility suggested by the frequency of aspartyl and glutamyl residues in its phosphoacceptor sites is that phosphorylation by CK2 could affect caspase cleavage that generally occurs at the carboxyl terminus of the acidic consensus E/D-x-D. At least five proteins (Max, Bid, connexin 45.6, HS1, and presenilin-2) have been reported to become refractory to caspase cleavage upon phosphorylation by CK2 (ref 219 and references therein). In the case of Bid, Max, and connexin, it has been shown that the residue phosphorylated by CK2 is very close to the cleavage site, suggesting that the adverse effect of CK2 is site directed. The ability of CK2 to antagonize the action of caspases can account, at least partially, for its anti-apoptotic role (7) .

Finally, a legitimate question would be whether CK2 contributes to the generation of protein–protein adhesion modules based on the recognition of phospho residues within given sequences. This kind of interaction is of paramount importance in signal transduction (220) . Although the first detected adhesion domains (SH2 and PTB) recognize phosphotyrosine, several motifs whose recognition is based on Ser/Thr phosphorylation were identified later (221) . Some of these are characterized by the pS/pT-P doublet, suggesting their generation by proline-directed kinases like CDKs or MAPKs and ruling out any implication of CK2. A scrutiny of the other Ser/Thr-phosphorylated consensuses known to act as adhesive modules supports the view that although there is no necessary dependance of any of these motifs on CK2 mediated phosphorylation, in some cases they are quite compatible with sequences phosphorylated by CK2 for including no negative determinants while welcoming or tolerating an acidic residue at position n+3. A notable example is provided by the phosphorylated motifs recognized by the WD40 domains, whose consensus is DpSGxx(x)S. This motif is found close to the carboxyl-terminal end of the ubiquitin-conjugating enzyme-2 CDC34/UBC3, where it also fulfills the conditions for undergoing phosphorylation by CK2 (DSGteeS). It has recently been shown that its phosphorylation by CK2 either in vitro or in vivo is indeed a prerequisite for the anchoring of UBC3 to the F-box receptor protein ß-TrCP (175) . The same applies to a homologue of UBC3, UBC3B, whose phosphorylation by CK2 at a similar site also confers the ability to bind ß-TrCP (175) . Note that at least two more CK2 sites listed in Table 3 , Ser-52 of HIV-1 Vpu protein and Ser-32 of I{kappa}B{alpha}, are located in a context conforming to the consensus recognized by WD40 domains.

The sequence recognized by the FHA domains xxxpTxxD/I/S/Y is also suited for CK2 mediated phosphorylation: it is actually found at 12 of the 42 Thr sites listed in Table 3 , although we do not know whether any of these sites has the function of interacting with FHA domains. In principle, even the motifs recognized by the 14–3-3 proteins, supposedly generated by basophilic kinases because of a conserved arginine at either n-3 or n-4 position, could be phosphorylated by CK2: the arginyl residue is in fact far away enough to be tolerated by CK2 and the motif Rxx(x)pS is found in 25 CK2 sites listed in Table 3 . In one case, homeodomain-containing transcription factor Csx, it is implemented by a proline at position n+2 that makes it a "perfect" 14–3-3 motif. In two other cases, DARPP-32 and PHAS-1, the motif is slightly altered (RxxxxpSxP and HxxxpSxP, respectively; see Table 3 ) but still reminiscent of the canonical one.


   CONCLUSIONS AND PERSPECTIVES
TOP
 ABSTRACT
 BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
REFERENCES
 
In the light of present knowledge, there is little doubt that CK2 is the most pleiotropic among the individual members of the protein kinase superfamily. Although "only" 307 proteins phosphorylated by CK2 are known (Table 1) , it is likely they are the tip of an iceberg. In fact, this figure is steadily increasing day after day at a rate that does not tend to decline. Second, the analysis of phosphoproteins in S. cerevisiae (214) suggests that CK2 phospho sites are more frequent than those generated by any other individual protein kinase and may contribute to as much as a quarter of the whole eukaryotic phosphoproteome. Third, a search based on CK2 consensus sequence discloses the possibility that many proteins that interact in vivo with CK2 are also potential substrates, although their phosphorylation has not been reported so far. In the future, we shall see a further dramatic increase of the already long list of CK2 substrates.

Such an extreme pleiotropism may provide the rationale to explain why CK2 is also constitutively active, and these two properties when taken together support the view that CK2 cannot be compared with any of the classical protein kinases that play specific roles by being turned on and off at individual steps of signaling pathways. Expectedly evidence will be accumulating that CK2 is committed to a global constitutive role within the cell, where it takes care of a wide variety of basal cellular functions, notably housekeeping gene expression, RNA synthesis, protein synthesis, and degradation, and survival response (7) . As discussed elsewhere (5) these physiological commitments of CK2 can become instrumental to dysregulated cell proliferation and virus infection under special circumstances. Whereas the majority of protein kinases operate in a hierarchical and "vertical" manner, along signaling cascades coming down from the membrane to the nucleus, CK2 intervenes laterally, like a free lance impinging on many signaling pathways at different levels. As first surmised 12 years ago (11) and recently corroborated by experimental data (6) in the case of CK2, the control of activity, if any, would take place in the opposite way from the other kinases, the paradigm "regulation = more activity" being subverted to "regulation = less activity." Using basket terminology, one would say that CK2 looks like a "playmaker" not a "pivot": hardly ever does it make scores; nevertheless, it is essential to the team game.

The systematic identification of all the proteins that are phosphorylated by CK2 (the "CK2 dependent phosphoproteome") will provide the pieces of the puzzle; next and not trivial task will be to put the pieces together and solve an enigma that has been lasting for nearly 50 years.


   ACKNOWLEDGMENTS
 
This work has been supported by grants from MIUR (Cofin 2001) and AIRC. We thank Dr. O. Marin for providing unpublished results.


   REFERENCES
TOP
 ABSTRACT
 BACKGROUND
 PROTEINS PHOSPHORYLATED BY CK2:...
 THE STIGMATA OF CK2...
 DO CK2 PHOSPHOACCEPTOR SITES...
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 

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