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Genomic overview of protein kinases*

Gerard Manning §
Razavi-Newman Center for Bioinformatics, Salk Institute for Biological Studies; La Jolla, California 92037 USA

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Table of Contents

1. Introduction
2. The C. elegans kinome
3. Kinase evolution
4. Recent expansions and inventions in the worm kinome
5. The C. briggsae kinome
6. Phosphatases
7. References
A. Appendix A: Classification of worm kinases


Protein kinases are one of the largest and most influential of gene families: constituting some 2% of the proteome, they regulate almost all biochemical pathways and may phosphorylate up to 30% of the proteome. Bioinformatics and comparative genomics were used to determine the C. elegans kinome and put it in evolutionary and functional context. Kinases are deeply conserved in evolution, and the worm has family homologs for over 80% of the human kinome. Almost half of the 438 worm kinases are members of worm-specific or worm-expanded families. Such radiations include genes involved in spermatogenesis, chemosensation, Wnt signaling and FGF receptor-like kinases. The C. briggsae kinome is largely similar apart from the expanded classes, showing that such expansions are evolutionarily recent.

1. Introduction

Protein kinases constitute one of the largest and most important of protein families, accounting for ~2% of genes in a variety of eukaryotic genomes. By phosphorylating substrate proteins, kinases modify the activity, location and affinities of up to 30% of all cellular proteins, and direct most cellular processes, particularly in signal transduction and co-ordination of complex pathways. Many of these pathways are highly conserved, and 53 distinct kinase functions and subfamilies appear to have been conserved between yeasts, nematodes, insects and vertebrates, with a further 91 subfamilies of kinases being seen throughout metazoan genomes. This makes kinase signaling particularly amenable to comparative studies, and kinase activity a particularly good readout of the physiological state of any cell.

This chapter will introduce the diversity of kinases in C. elegans, and compare them to those of fungi and other metazoans, as well as to preliminary results from analysis of the C. briggsae kinome.

2. The C. elegans kinome

Most protein kinases share a common ePK (eukaryotic protein kinase) catalytic domain, and can be identified by sequence similarity with Blast or profile hidden Markov models (HMMs). The remaining atypical protein kinases (aPK) belong to several families, some of which have structural, but not sequence similarity to ePKs. We used ePK and aPK HMMs, and Blast/psi-Blast with divergent kinase sequences, to identify protein kinase sequences in C. elegans genomic and expressed sequences (Manning et al., 2002; Plowman et al., 1999). We identified 438 protein kinase genes, including 20 atypical kinases, and an additional 25 kinase fragments or pseudogenes. All sequences and supporting data are available at http://kinase.com, and all but 8 sequences are now identical to wormpep (v. 141) sequences.

3. Kinase evolution

To put worm kinases into an evolutionary and functional context, we compared them with the distant kinomes of human, fly, and yeast. At these distances, 1:1 orthology is rare, so we classified each kinase into a hierarchy of groups, families, and sometimes subfamilies (Manning et al., 2002a; Manning et al., 2002b). The classification is based on sequence similarity within the kinase domain, the presence of additional domains, known biological functions, and conservation across divergent genomes. Across the four kinomes, there are 10 groups, 143 families and 212 subfamilies. The classification of each worm kinase is given in Appendix A.

Since kinases perform such a variety of distinct basic cellular functions, it is not surprising to see that 53 subfamilies and functions are present in all four kinomes (Figure 1). A further 91 subfamilies were found in all three metazoan kinomes, including the tyrosine kinase (TK) group and the TKL group, which mediate much of the complexity of intercellular signal transduction. The gain and loss of kinase functions and subfamilies in each evolutionary lineage is also seen. In general, the data support the coelomate clade, where insects are more closely related to vertebrates than to nematodes, rather than the ecdysozoa clade, which groups insects and nematodes together.

figure 1

Figure 1. Distribution of 212 kinase subfamilies throughout four kinomes: the yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and human.

Nematodes share 153 subfamilies with human, providing close homologs for 81% (419/518) of all human kinases. 6 families appear to have been lost from nematodes, based on their presence in fly, human and more basal organisms (Table 1), and several new families have been invented within the coelomate lineage, whose functions predominantly map to immunity/angiogenesis, neurobiology, cell cycle and morphogenesis. There are 13 such human-specific families, and 16 shared between fly and human.

Table 1. Kinases lost in worm, or gained in fly or human kinomes.

Group Family Subfamily Fly count Human count Function Notes
Secondarily lost from worm
Atypical G11   1 1 Unknown Also in yeast and plants
CAMK CAMKL PASK 1 1 Glucose sensor Also in yeast
Other TTK   1 1 Cell cycle Also in yeast and plants
Atypical PIKK DNAPK 1 1 DNA repair Also in Dictyostelium
Atypical TIF   1 3 Transcriptional control Also in Dictyostelium. NHR co-factor
TK CCK4   1 1 Neuronal; cell growth Also in Hydra. Neuronal pathfinding; cancer
Fly + Human
CAMK Trbl   1 3 Cell cycle  
CMGC CDK CDK10 1 1 Cell cycle?  
Other IKK   2 4 Immunity NFkb signaling
Other MOS   1 1 Cell cycle Meiosis
Other SLOB   2 1 Neuronal Synaptic transmission
Other TOPK   1 1 Cell cycle  
STE Ste20 NinaC 1 2 Neuronal Phototransduction
TK Jak   1 4 Immunity Cytokine signaling
TK Musk   1 1 Neuronal Synaptic transmission
TK PDGFR/ VEGFR   2 8 Angiogenesis; morphogenesis; immunity  
TK Ret   1 1 Immunity, development Growth factor receptor
TK Sev   1 1 Morphogenesis  
TK Syk   1 2 Immunity; morphogenesis  
TK Tec   1 5 Immunity; morphogenesis  
TKL LISK LIMK 1 2 Cytoskeletal  
TKL LISK TESK 1 2 Testis development  
Atypical Alpha ChaK 0 2 Neuronal Human adds kinase to metazoan-wide channel
Atypical BCR   0 1 Cell growth Ras/MAPK growth factor responses
Atypical FAST   0 1 Apoptosis  
Atypical H11   0 1 Apoptosis?  
CAMK CAMKL HUNK 0 1 Development Mammary gland development
CAMK Trio   0 6 Muscle Human adds kinase to conserved protein
Other NKF3   0 2 Unknown  
Other NKF4   0 2 Cytoskeletal  
Other NKF5   0 2 Testis development?  
TK Axl   0 3 Cell growth; adhesion  
TK Lmr   0 3 Cell growth?  
TK Tie   0 2 Angiogenesis  
TKL RIPK   0 5 Immunity  

On the other hand, the worm shares eight subfamilies with human which are absent from Drosophila (Table 2). These include two receptor tyrosine kinase families, an atypical elongation factor 2 kinase (eEF2K), several members of the CAMK group (MELK, PSK, PIM) and the HH498 subfamily of Mixed Lineage Kinases (MLK). In some but not all cases, the fly genome has related genes that may fulfill a similar function. SGK, eEF2K and HH498 are found in Dictyostelium, and ABC1-C in yeast, reinforcing their secondary loss from insects. The secondary loss of conserved kinases within each lineage highlights how essential functions are dependent on the context of other genes and pathways in the organism.

Table 2. Kinase subfamilies shared by worm and human, but not fly.

Group Family Subfamily Worm genes Human genes Notes
AGC SGK   1 3 Close relative to the AKT (PKB) family
Atypical ABC1 ABC1-C 1 1 Other ABC1 subfamilies may compensate.
Atypical MHCK eEF2K 1 1 Eukaryotic elongation factor 2 kinase.
CAMK CAMKL MELK 1 1 MELK is an outgroup of MARK, which is present in fly. Splicing function?
CAMK PSK   1 2 Human PSKH1 has a Golgi function.
CAMK PIM   2 3 Related to PASK, which is present in fly and absent from worm.
TKL MLK HH498 1 1 Human form is cardiac-specific, worm is neuronal-restricted. Divergent functions?
TK Trk   1 3 Neurotrophin receptor. Fly has closely related Ror and Musk families.
TK Met   2 2 Worm has a clear Met homolog and a divergent family member.

4. Recent expansions and inventions in the worm kinome

The C. elegans kinome is also marked by a dramatic expansion of a small number of kinase classes. C. elegans has almost twice as many kinases as Drosophila (438 vs. 241 genes), but virtually all the difference (195 of 197 genes) is accounted for by expansions of a small number of families and of worm-specific families.

Fifteen kinase subfamilies are nematode-specific, accounting for almost a quarter of the kinome (105 genes). They include 8 distinct subfamilies within a large expansion of CK1 group kinases, containing 78 kinases, and two FGFR-like receptor tyrosine kinase families. An additional 5 families are in the Other group, and have very little similarity to any non-worm kinases. In general, they are not well characterized.

Table 3. Worm-specific and worm-expanded kinase classes. Counts of genes in kinomes. C. briggsae data from unpublished analysis of genome-predicted peptides.

Name/Classification C. elegans C. briggsae Fly Human
CK1/Dual 3 3 0 0
CK1/TTBKL 31 22 0 0
CK1/Worm6 28 19 0 0
CK1/Worm7 2 1 0 0
CK1/Worm8 3 1 0 0
CK1/Worm9 2 0 0 0
CK1/Worm10 2 2 0 0
CK1/Worm11 1 2 0 0
CK1/Unique 6 3 0 0
TK/Fer 38 24 1 2
RGC group 27 20 6 5
TK/KIN-16 16 6 0 0
Other/Haspin 13 1 1 1
CMGC/GSK3 7 6 3 2
CAMK/CAMKL/ CHK1 7 1 1 1
Ste/Ste7 10 8 4 7
CMGC/MAPK/Jnk 5 3 1 3
TK/KIN-9 5 5 0 0
Other/Worm1 2 1 0 0
Other/Worm2 3 2 0 0
Other/Worm3 2 1 0 0
Other/Worm4 1 1 0 0
Other/Worm5 3 0 0 0
Total 217 132 17 21

These kinases may hold a key to several nematode-specific biological functions. In several cases, the expansions appear recent, as the members are closely related by sequence and chromosomal location, and several appear to have been generated since the C. elegans/C. briggsae split. Many may have reduced or no function: several have lost catalytic or other conserved residues and 20 of the 25 worm kinase pseudogenes are from these families, indicating a high rate of gene turnover. A similar expansion is seen in C. briggsae, and though it appears that this is more modest, some of this may be due to the preliminary nature of the annotation and kinase analysis of this genome.

Reproductive functions often drive rapid evolution, and there is some evidence implicating kinase expansions in nematode spermatogeneis. One CK1 gene (spe-6) and one Fer gene (spe-8) function in spermatogenesis, and half or more of these classes are selectively expressed in sperm by microarray analysis (Muhlrad and Ward, 2002; Reinke et al., 2000; P. Muhlrad and S. Ward, pers. commun.).

Receptor guanylate cyclases (RGC) have a catalytically inactive kinase domain, and have separately expanded in all three metazoans, but most dramatically in worm (Morton, 2004). Most are uncharacterized, but several are expressed in highly restricted sets of neurons and are implicated in chemosensation, and one (daf-11) is involved in dauer formation (Vowels and Thomas, 1992).

The KIN-9 (previously known as kin-6) and KIN-16 families encode receptor tyrosine kinases, whose kinase domains and overall structure most resemble the FGF receptor family. Some of the KIN-16 family have arrays of extracellular immunoglobulin repeats, and some have vestigial extracellular regions (Popovici et al., 1999), while KIN-6 members have diverse novel extracellular regions. KIN-16 includes the old-1 and old-2 genes thought to be involved in age and stress resistance (Rikke et al., 2000). Many of the KIN-16 genes are chromosomally clustered, and are poorly conserved in C. briggsae, indicating a recent origin (Figure 2A). The KIN-9 genes are not clustered and all have briggsae orthologs.

 figure 2

Figure 2. Orthology between C. elegans and C. briggsae kinases. Squares indicate likely orthologous pairs of kinases, and circles denote paralogous expansions. C. briggsae sequences are predictions (CBGnnnnn) from the genome project. (A) In the worm-specific KIN-16 family, new genes continue to arise in the elegans and briggsae lineages, as indicated by circles. (B) In the CDK family, all 13 members exist as orthologous pairs and subfamilies (labeled) are also conserved in Drosophila and human.

Of the 7 GSK3 members, 6 have clear briggsae homologs, but only one (gsk-3) has been characterized, and it acts in a defined Wnt signaling pathway (Schlesinger et al., 1999). The additional members may act in an expanded Wnt-like pathway, as worms have other duplicated pathway members including three members each of the beta-catenin and dishevelled families. Both CK1 and Fer kinases are implicated in mammalian Wnt signaling, and some of their worm expansions may also function in this pathway. The role of GSK3 in insulin signaling may also correlate with the expansion of insulin genes in nematodes.

The expansion of the Jnk stress-response MAPK family is partially paralleled by the expansion of the MAPKK (Ste7) family, which now includes 4 putative Jnk kinases (JNKKs).

5. The C. briggsae kinome

A preliminary analysis of C. briggsae predicted proteins (release 25; Stein et al., 2003) indicates the presence of 341 kinase genes, using the C. elegans kinome as blast query set. An additional 30 or more kinases or kinase fragments were detected by direct search of the genome, but are still poorly predicted. The majority (320) of C. briggsae kinases appear orthologous to a single C. elegans kinase, by bidirectional blast searches. The main differences between the two kinomes are in the recently-expanded families, where the expansion appears to have continued since the elegans/briggsae split. Of 21 briggsae-unique kinases, 19 are from expanded families, and 98 of 117 elegans-unique kinases are from expanded families. More thorough sequence analysis will likely reveal more briggsae kinases and more ortholog pairs, but this data does strongly support both continued gene birth and death, and sequence diversification, within these expanded families. The difference between conserved and expanded families is shown in Figure 2A of the nematode-specific KIN-16 family, in which few pairs of obvious orthologs are seen between the two species. By contrast, the CDK family has 13 members in both species, all of which pair off in an orthologous fashion (Figure 2B).

6. Phosphatases

Phosphatases remove phosphates from kinase substrates, both reversing kinase-based activation, and relieving kinase-mediated repressions. Phosphatases belong to several different families, including a number of distinct phosphatase domains: the PTP (protein tyrosine phosphatase), DSP (dual-specificity phosphatase which dephosphorylates both tyrosine and serine/threonine) and several families of STP, or serine-threonine phosphatases. While ‘phosphatome’ analysis lags behind that of the kinomes, an initial survey of C. elegans phosphatases identified 83 PTPs, 26 DSPs and 65 STPs (Plowman et al., 1999). The completion of two nematode genomes and multiple other eukaryotic genomes now opens the door for comparative analysis to identify additional C. elegans phosphatases and to compare their distribution with those of other organisms, and with the expansions of their cognate kinomes.

7. References

Manning, G., Plowman, G.D., Hunter, T., and Sudarsanam, S. (2002a). Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514–520. Abstract Article

Manning, G., Whyte, D.B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002b). The protein kinase complement of the human genome. Science 298, 1912–1934. Abstract Article

Morton, D.B. (2004). Invertebrates yield a plethora of atypical guanylyl cyclases. Mol. Neurobiol. 29, 97–116. Abstract

Muhlrad, P.J., and Ward, S. (2002). Spermiogenesis initiation in Caenorhabditis elegans involves a casein kinase 1 encoded by the spe-6 gene. Genetics 161, 143–1550. Abstract

Plowman, G.D., Sudarsanam, S., Bingham, J., Whyte, D., and Hunter, T. (1999). The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. Proc. Natl. Acad. Sci. USA 96, 13603–13610. Abstract Article

Popovici, C., Roubin, R., Coulier, F., Pontarotti, P., and Birnbaum, D. (1999). The family ofCaenorhabditis elegans tyrosine kinase receptors: similarities and differences with mammalian receptors. Genome Res. 9, 1026–1039. Abstract

Reinke, V., Smith, H.E., Nance, J., Wang, J., Van Doren, C., Begley, R., Jones, S.J., Davis, E.B., Scherer, S., Ward, S., and Kim, S.K. (2000). A global profile of germline gene expression in C. elegans. Mol. Cell 6, 605–616. Abstract

Rikke, B.A., Murakami, S., and Johnson, T.E. (2000). Paralogy and orthology of tyrosine kinases that can extend the life span of Caenorhabditis elegans. Mol. Biol. Evol. 17, 671–683. Abstract

Schlesinger, A., Shelton, C.A., Maloof, J.N., Meneghini, M., and Bowerman, B. (1999). Wnt pathway components orient a mitotic spindle in the early Caenorhabditis elegans embryo without requiring gene transcription in the responding cell. Genes Dev. 13, 2028–2038. Abstract

Stein, L.D., Bao, Z., Blasiar, D., Blumenthal, T., Brent, M.R., Chen, N., Chinwalla, A., Clarke, L., Clee, C., Coghlan, A., et al. (2003). The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol. 1, E45. Abstract Article

Vowels, J.J., and Thomas, J.H. (1992). Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 130, 105–123. Abstract

A. Appendix A: Classification of worm kinases

Table 4. Classification of worm kinases

Group Family Subfamily # Kinases (domains) Distribution Names Other Wormbook entries Name/ function overview
AGC     2 Nematodes, Dictyostelium F31E3.2, F28C10.3    
AGC AKT   2 All kinomes akt-1, akt-2   PI3K signaling
AGC DMPK GEK 1 All metazoans K08B12.5   Myotonic dystrophy protein kinase
AGC DMPK ROCK 1 Metazoans, Dictyostelium let-502   Myotonic dystrophy protein kinase/Rho kinase
AGC GRK BARK 1 All metazoans grk-2   Beta adrenergic receptor kinase
AGC GRK GRK 1 All metazoans grk-1   G protein coupled kinase
AGC MAST   1 Metazoans, Dictyostelium kin-4   Microtubule associated serine/ threonine kinase
AGC NDR   2 All kinomes sax-1, T20F10.1    
AGC PDK1   2 All kinomes pdk-1, W04B5.5   PI3K signaling
AGC PKA   2 All kinomes kin-1, F47F2.1   cAMP-dependent protein kinase
AGC PKC Alpha 1 All metazoans pkc-2   Protein kinase C isoforms
AGC PKC Delta 1 All metazoans tpa-1   Protein kinase C isoforms
AGC PKC Eta 1 All metazoans kin-13   Protein kinase C isoforms
AGC PKC Iota 1 All metazoans pkc-3   Protein kinase C isoforms
AGC PKG   2 All metazoans egl-4, C09G4.2   cGMP-dependent protein kinase
AGC PKN   1 All metazoans F46F6.2   Protein kinase N
AGC RSK MSK 1 All metazoans C54G4.1   Ribosomal S6 kinase
AGC RSK p70 2 Metazoans, fungi Y43D4A.6, R04A9.5   Ribosomal S6 kinase
AGC RSK RSK 1 All metazoans T01H8.1a   Ribosomal S6 kinase
AGC RSKL   1 All metazoans F55C5.7   Ribosomal S6 kinase-like
AGC SGK   1 Nematodes, vertebrates, dictyostelium W10G6.2   Serum/glucocorticoid-regulated kinase
AGC YANK   1 All metazoans M03C11.1   Uncharacterized
Atypical A6   2 All kinomes unc-60, F38E9.5    
Atypical ABC1 ABC1-A 1 All kinomes C35D10.4    
Atypical ABC1 ABC1-B 1 All kinomes D2023.6    
Atypical ABC1 ABC1-C 1 All but insects Y32H12A.7    
Atypical Alpha eEF2K 1 Nematodes, vertebrates, dictyostelium efk-1   Elongation factor 2 kinase
Atypical BRD   3 Metazoans, Dictyostelium Y119C1B.8, F57C7.1b, F13C5.2   Bromodo-main-containing kinase
Atypical PDHK   2 Metazoans, fungi ZK370.5, aSWK467   Pyruvate dehydrogenase kinase
Atypical PIKK ATM 1 Metazoans, fungi atm-1   DNA damage response
Atypical PIKK ATR 1 All kinomes atl-1   DNA damage response
Atypical PIKK FRAP 1 All kinomes B0261.2   Metabolic regulation (aka TOR)
Atypical PIKK SMG1 1 Metazoans, Dictyostelium smg-1   mRNA surveillance
Atypical PIKK TRRAP 1 All kinomes C47D12.1    
Atypical RIO RIO1 1 All kinomes M01B12.5    
Atypical RIO RIO2 1 All kinomes Y105E8B.3    
Atypical RIO RIO3 1 All metazoans ZK632.3    
Atypical TAF1   1 All kinomes taf-1   Basal transcription: TFIID associated factor.
CAMK CAMK1   1 All kinomes cmk-1   Calmodulin-dependent protein kinase 1
CAMK CAMK2   1 All metazoans unc-43   Calmodulin-dependent protein kinase 1
CAMK CAMKL AMPK 2 All kinomes aak-1, aak-2   Metabolic regulation
CAMK CAMKL BRSK 1 Metazoans, Dictyostelium sad-1   Neuronal vesicle release
CAMK CAMKL CHK1 5 (7) Metazoans, fungi chk-1, Y43D4A.6, R02C2.1, R02C2.2, DC2.7   Cell cycle checkpoint kinase 1
CAMK CAMKL LKB 1 Metazoans, Dictyostelium par-4   Activator of AMPK
CAMK CAMKL MARK 2 All kinomes par-1, F23C8.8 Asymmetric cell division and axis formation in the embryo Microtubule affinity regulating kinase
CAMK CAMKL MELK 1 Nematodes and vertebrates W03G1.6   Maternal embryonic leucine zipper kinase
CAMK CAMKL NIM1 1 All metazoans F49C5.4    
CAMK CAMKL NuaK 1 All metazoans B0496.3   Uncharacterized
CAMK CAMKL QIK 1 Metazoans, Dictyostelium kin-29   Qin induced kinase
CAMK CAMKL SNRK 1 All metazoans ZK524.4    
CAMK CASK   1 All metazoans lin-2    
CAMK DAPK   1 All metazoans K12C11.4   Death-associated protein kinase
CAMK DCAMKL   2 All metazoans zyg-8, F32D8.1   Doublecortin and CAMK-like
CAMK MAPKAPK MAPKAPK 2 All metazoans K08F8.1, C44C8.6   MAPK activated protein kinase
CAMK MAPKAPK MNK 1 All metazoans R166.5   MAPK activated protein kinase
CAMK MLCK   4 (5) All metazoans unc-22, C24G7.5, ZC373.4, F12F3.2   Myosin light chain kinase
CAMK PHK   1 All metazoans Y50D7A.3   Phosphorylase kinase
CAMK PIM   2 Nematodes and vertebrates prk-1, prk-2    
CAMK PKD   2 All metazoans T25E12.4, W09C5.5   Protein kinase D
CAMK PSK   1 Nematodes and vertebrates R06A10.4   Protein serine kinase
CAMK RAD53   2 Metazoans, fungi chk-2, T08D2.7   DNA damage checkpoint
CAMK RSKb MSKb 0(1) All metazoans C54G4.1   Second domain of RSK kinases
CAMK RSKb RSKb 0(1) All metazoans T01H8.1a   Second domain of RSK kinases
CAMK TSSK   3 All metazoans B0511.4, W02B12.12, Y38H8A.4   Testis-specific serine kinase
CK1 Unique   6 Some metazoans T15B12.2, ZK507.3, C25H3.1, F16B12.5, ZK507.1, K09E4.1    
CK1 CK1 CK1-A 1 All metazoans C03C10.1   Cell kinase 1/Casein kinase 1
CK1 CK1 CK1-D 1 All kinomes F46F2.2   Cell kinase 1/Casein kinase 1
CK1 CK1 CK1-G 1 Metazoans, fungi Y106G6E.6   Cell kinase 1/Casein kinase 1
CK1 Dual   3 (6) Nematodes F59A6.4, T05A7.6, H05L14.1   Dual-domain CK1 kinase subfamily
CK1 TTBK   1 Metazoans, Dictyostelium R90.1   Tau tubulin kinase
CK1 TTBKL   31 Nematodes M7.7, B0207.7, F35C11.3, Y71F9AL.2, C04G2.2, C45G9.1, F32B6.10, W01B6.2, C05C12.1, C49C8.1, Y73B6A.2, D2024.1, Y47G6A.13, F54H5.2, C56C10.6, C53A5.4, K06H7.8, D2045.5, W09C3.1, R10D12.10, T11F8.4, ZC581.2, T05C12.1, W06F12.3, C03C10.2, T19D12.5, ZK666.8, ZK354.6, F26A1.4, C14A4.13, W03G9.5   Tau tubulin kinase-like
CK1 VRK   1 All metazoans F28B12.3   Vaccinia-related kinase
CK1 Worm10   2 Nematodes F26A1.3, F25F2.1   Uncharacterized
CK1 Worm11   1 Nematodes K11C4.1   Uncharacterized
CK1 Worm6   28 Nematodes Y38H8A.3, C39H7.1, ZK596.2, C50F4.10, C08F8.6, F36H12.8, R13H9.5, Y69F12A.1, B0218.5, F36H12.9, R13H9.6, T09B4.7, C09D4.3, C55B7.10, F41G3.5, F38E1.3, C27D8.1, Y39G8C.2, F53C3.1, F33D11.7, C34B2.3, C49C3.2, spe-6, C09B9.4, ZK354.2, Y65B4A.9, F59E12.3, C38C3.4   Uncharacterized
CK1 Worm7   2 Nematodes T01H10.4, ZC373.3   Uncharacterized
CK1 Worm8   3 Nematodes F22F1.2, F39F10.3, F39F10.2   Uncharacterized
CK1 Worm9   2 Nematodes K04C1.5, E02H4.6   Uncharacterized
CMGC     1 Nematodes, fungi F52B5.2    
CMGC CDK   1 Metazoans, fungi H01G02.2   Cyclin dependent kinase
CMGC CDK CDC2 2 All kinomes cdk-1, K03E5.3   Cell cycle: cyclin dependent kinase
CMGC CDK CDK4 1 All metazoans cdk-4   Cell cycle: cyclin dependent kinase
CMGC CDK CDK5 1 All metazoans cdk-5   Cyclin dependent kinase
CMGC CDK CDK7 1 All kinomes cdk-7   Cell cycle: cyclin dependent kinase
CMGC CDK CDK8 1 All kinomes F39H11.3   Cell cycle: cyclin dependent kinase
CMGC CDK CDK9 1 All metazoans H25P06.2   Cell cycle: cyclin dependent kinase
CMGC CDK CRK7 1 All kinomes B0285.1   Cell cycle: cyclin dependent kinase
CMGC CDK PITSLRE 2 Metazoans, Dictyostelium ZC504.3, B0495.2   Cell cycle: cyclin dependent kinase
CMGC CDK TAIRE 2 All metazoans pct-1, ZC123.4   Cell cycle: cyclin dependent kinase
CMGC CDKL   1 All metazoans Y42A5A.4   Cyclin dependent kinase-like
CMGC CLK   3 All kinomes C16A11.3, Y111B2A.1, E02H4.3   CDC-like kinase, involved in splicing
CMGC Dyrk Dyrk1 1 Metazoans, Dictyostelium mbk-1    
CMGC Dyrk Dyrk2 3 Metazoans, Dictyostelium mbk-2, C36B7.1, C36B7.2    
CMGC Dyrk HIPK 1 All metazoans hpk-1   Hypoxia-inducible protein kinase
CMGC Dyrk PRP4 1 Metazoans, Dictyostelium F22D6.5   mRNA processing
CMGC GSK   7 All kinomes gsk-3, R03D7.5, Y106G6D.4, C44H4.6, Y106G6E.1, C36B1.10, F21F3.2   Glycogen synthase kinase 3
CMGC MAPK   3 Some metazoans W06B3.2, F09C12.2, C04G6.1    
CMGC MAPK Erk 1 All kinomes mpk-1 RTKRas/ MAP kinase signaling Growth factor response MAPK
CMGC MAPK Erk7 1 Metazoans, Dictyostelium C05D10.2   Variant MAPK
CMGC MAPK Jnk 5 All metazoans jnk-1, T07A9.3, Y51B9A.9, ZC416.4, C49C3.10 Signaling in the immune response Stress-response MAPK
CMGC MAPK nmo 1 All metazoans lit-1   Variant MAPK
CMGC MAPK p38 3 Metazoans, fungi pmk-1, pmk-2, pmk-3   Stress-response MAPK
CMGC RCK   1 All kinomes M04C9.5    
CMGC SRPK   1 All kinomes spk-1   mRNA splicing
Other Unique   10 All kinomes flr-4, zyg-1, Y106G6A.1, D2045.7, K09A9.1, Y53F4B.1, K11H12.9, K02E10.7, F37E3.3, C29H12.5    
Other Aur   2 All kinomes air-1, air-2   Cell cycle/chromosomal stability
Other Bub   1 All kinomes bub-1   Cell cycle
Other Bud32   1 All kinomes F52C12.2   Essential homolog of yeast Bud32.
Other CAMKK Meta 1 Metazoans, Dictyostelium ckk-1   CAMK kinase
Other CDC7   1 All kinomes C34G6.5   Variant cyclin-dependent kinase
Other CK2   1 All kinomes B0205.7   Cell kinase 2/Casein kinase 2
Other Haspin   13 All kinomes Y18H1A.10, K08B4.5, C50H2.7, T05E8.2, ZK177.2, H12I13.1, Y48B6A.10, C01H6.9, F22H10.5, C04G2.10, Y40A1A.1, Y73B6A.1, aSWK457   Nuclear kinase; meiosis?
Other IRE   1 All kinomes ire-1   Unfolded protein response
Other Nak   2 All kinomes sel-5, F46G11.3    
Other Nek   4 All kinomes F19H6.1, ZC581.1, Y39G10AR.3, pqn-25,   Cell cycle (NIMA-related kinase)
Other NKF1   1 All metazoans C01C4.3   Uncharacterized
Other NKF2   1 All metazoans EEED8.9   Uncharacterized
Other NRBP   1 All metazoans K10D3.5   Nuclear receptor binding protein
Other PEK GCN2 1 All kinomes Y81G3A.3    
Other PEK PEK 2 Metazoans, Dictyostelium pek-1, Y38E10A.8    
Other PLK   3 All kinomes plk-1, plk-2, F55G1.8   Cell cycle: polo-like kinase
Other SCY1   2 All kinomes W07G4.3, ZC581.9    
Other TBCK   1 Metazoans, Dictyostelium C33F10.2   TBC domain kinase
Other TLK   1 All metazoans C07A9.3   Tousled-like kinase
Other ULK   2 All kinomes unc-51, T07F12.4   Homolog of Drosophila Fused
Other VPS15   1 All kinomes ZK930.1    
Other WEE   2 All kinomes wee-1.1, wee-1.3   Cell cycle
Other Wnk   1 All metazoans C46C2.1   With no lysine[K]
Other Worm1   2 Nematodes mes-1, B0198.3   Uncharacterized
Other Worm2   3 Nematodes K09C6.8, T10B5.2, K09C6.7   Uncharacterized
Other Worm3   2 Nematodes R107.4, Y39G8B.5   Uncharacterized
Other Worm4   1 Nematodes C28A5.6   Uncharacterized
Other Worm5   3 Nematodes C44C10.7, F16B12.7, K08H2.5   Uncharacterized
RGC RGC   27 All metazoans gcy-13, gcy-14, odr-1, gcy-19, gcy-15, gcy-9, daf-11, T01A4.1b, gcy-4, gcy-17, gcy-3, gcy-7, C04H5.4a, gcy-11, gcy-18, gcy-25, gcy-21, gcy-27, gcy-23, gcy-1, gcy-20, gcy-5, gcy-6, gcy-8, gcy-22, gcy-2, gcy-12   Receptor guanylate cyclase
STE Unique   1 Metazoans, Dictyostelium F18F11.4    
STE Ste11   2 All kinomes nsy-1, B0414.7   MAP kinase kinase kinase
STE Ste20 FRAY 1 Metazoans, Dictyostelium Y59A8B.23   MAP4 kinase and related
STE Ste20 KHS 1 All metazoans ZC404.9   Subfamily of MAP4K kinases
STE Ste20 MSN 1 All metazoans ZC504.4   Subfamily of MAP4K kinases
STE Ste20 MST 1 All kinomes F14H12.4   Subfamily of MAP4K kinases
STE Ste20 PAKA 2 All kinomes C09B8.7, Y38F1A.1   Couples small GTPases to cytoskeleton
STE Ste20 PAKB 1 All metazoans C45B11.1   Couples small GTPases to cytoskeleton
STE Ste20 SLK 1 All metazoans C04A11.3   Subfamily of MAP4K kinases
STE Ste20 STLK 2 All metazoans C03B1.5, Y52D3.1   Subfamily of MAP4K kinases
STE Ste20 TAO 1 All metazoans T17E9.1   Subfamily of MAP4K kinases
STE Ste20 YSK 1 Metazoans, fungi T19A5.2   Subfamily of MAP4K kinases
STE Ste7   10 All kinomes jkk-1, mek-1, mek-2, sek-1, mkk-4, ZC449.6, VZC374L.1, E02D9.1a, F35C8.2, F35C8.1 RTKRas/ MAP kinase signaling MAP kinase kinase
TK Unique   7 All metazoans C16D9.2, Y38H6C.20, F40A3.5, F59F5.3, R151.4, C34F11.5, T22B11.3    
TK Abl   1 All metazoans abl-1   Abelseon leukemia virus homolog
TK Ack   2 All metazoans ark-1, kin-25    
TK Csk   1 All metazoans Y48G1C.2    
TK Fer   38 All metazoans frk-1, spe-8, kin-5, kin-14, kin-21, kin-24, kin-26, kin-28, aSWK454, Y43C5B.2, Y116A8C.24, K09B11.5, Y52D5A.2, Y69E1A.3, T25B9.5, M176.9, ZC581.7, F59A3.8, R05H5.4, W01B6.5, T08G5.2, F57B9.8, T21G5.1, C25A8.5, T06C10.3, F22B3.8, F01D4.3, W03F8.2, ZK622.1, R11E3.1, T25B9.4, ZK593.9, F26E4.5, W03A5.1, C35E7.10, C55C3.4, C18H7.4, F23C8.7    
TK Src   3 All metazoans src-1, src-2, Y47G6A.5a   Non-receptor tyrosine kinase
TKL IRAK   1 All metazoans K09B11.1   IL-1 receptor associated kinase
TKL LRRK   1 Metazoans, Dictyostelium T27C10.5   Leucine rich repeat kinase
TKL MLK HH498 1 Nematodes, vertebrates, Dictyostelium C24A1.3   Uncharacterized
TKL MLK ILK 1 All metazoans C29F9.7   Integrin linked kinase
TKL MLK LZK 1 All metazoans F33E2.2    
TKL MLK MLK 2 Metazoans, Dictyostelium Y58A7A.f, R13F6.7   Mixed lineage kinase
TKL MLK TAK1 2 All metazoans F52F12.3, Y105C5.y    
TKL RAF   3 All metazoans raf-1, pex-1, ksr-1 RTKRas/ MAP kinase signaling Ras-MAPK signaling
TKL STKR Type1 2 All metazoans sma-6, daf-1 TGF-β signaling TGFb and related receptors
TKL STKR Type2 1 All metazoans daf-4 TGF-β signaling TGFb and related receptors
TK-RTK Alk   1 All metazoans scd-2    
TK-RTK DDR   2 All metazoans F11D5.3, C25F6.4   Discoidin domain receptor.
TK-RTK EGFR   1 All metazoans let-23 RTKRas/ MAP kinase signaling Growth factor (EGF) receptor
TK-RTK Eph   1 All metazoans vab-1   Ephrin receptor
TK-RTK Fak   1 All metazoans kin-32   Focal adhesion kinase
TK-RTK FGFR   1 All metazoans egl-15 RTKRas/ MAP kinase signaling Growth factor FGF) receptor
TK-RTK InsR   1 All metazoans daf-2   Insulin receptor
TK-RTK KIN-16   15 (16) Nematodes old-1, old-2, ver-1, R09D1.13, kin-23, T17A3.8, T01G5.1, C08H9.8, F59F3.1, M176.7, F59F3.5, M176.6, kin-30, R09D1.12, Y50D4B.6   Uncharacterized
TK-RTK KIN-9   5 Nematodes F09G2.1, F09A5.2, C24G6.2, F08F1.1, B0252.1   Uncharacterized
TK-RTK Met   2 Nematodes and vertebrates F11E6.8, T14E8.1   Growth factor (HGF/SF) receptor
TK-RTK Ror   1 All metazoans cam-1   Receptor tyrosine kinase
TK-RTK Ryk   1 All metazoans C16B8.1    
TK-RTK Trk   1 Nematodes and vertebrates D1073.1   Neurotropin receptor
TOTAL     438(447)        

*Edited by Iva Greenwald. Last revised December 10, 2005. Published December 13, 2005. This chapter should be cited as: Manning, G. Genomic overview of Protein Kinases (December 13, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.60.1, http://www.wormbook.org.

§To whom correspondence should be addressed. E-mail: manning@salk.edu

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