The 43 species considered here span a number of phylogenetic lineages, genome sizes and display a range of adaptations to their environment. The genome-wide kinase group assignments are consistent with our previously published results (6
) in that seven protein kinase groups (AGC, CAMK, CK1, CMGC, STE, PIKK and RIO) are present in all species surveyed () and some kinases in these groups are likely to be essential. Kinases of the groups RGC, TK, TKL, Alpha and PDHK are late innovations in specific phyla or have been lost secondarily in specific lines of descent. The presence of a discrete number of putative TKs in photosynthetic organisms and the pathogen Entamoeba histolytica
suggests that TKs are also likely to have had an ancient origin. This observation has recently been strengthened by the finding of animal-like signalling molecules in the green alga Chlamydomonas reinhardtii
). These include scavenger receptor cysteine rich (SRCR) and C-type lectin domain (CTLD) proteins, both of which play key roles in the innate immune system of metazoa. The identification of SH2 domain proteins in photosynthetic organisms (63
) suggests that phosphotyrosine-SH2 domain signalling also has an ancient origin and that important cell signalling and adhesion domains evolved before the divergence of the animal lineage.
The observation that many species outside the Opisthokont group lack important kinase groups, as is the case of TKs in Apicomplexa (Miranda-Saavedra, D. et al.
, manuscript submitted for publication), and which have many lineage-specific groups of kinases, suggests that the group level is the most specific level for the automatic classification of kinomes based on models constructed from sequences outside the taxonomic clade under investigation. With the availability of a number of Deuterostome, Protostome and pre-bilaterian genome sequences, having all kinases belonging to a particular kinase group enables novel analyses to be performed. For example, it is now possible to trace the evolution of receptor tyrosine kinase families and that of their ligands. Since receptor tyrosine kinases are multi-domain proteins, diverging rates of evolution of the various domains, and their incorporation in the receptor molecule in select phylogenetic lineages, is informative of distinct selection pressures and can be informative of newly acquired functions through the acquisition of new ligand-binding domains. This is the case with the Trk family of receptor tyrosine kinases, which encode the neurotrophin receptors [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4)]. The neurotrophin receptors are an ancient family whose function has been lost in multiple lineages and the roles of the receptors have been modified over time (65
Kinomer v. 1.0 also includes the manually annotated kinomes of the model fungi S. cerevisiae
and S. pombe
, and that of the unicellular fungi-like parasite Encephalitozoon cuniculi
). We have recently shown that the two model fungi share ~85% of their kinomes (53
), a degree of similarity much higher than that previously reported. The kinomes of budding and fission yeasts are therefore a useful dataset for annotating the kinomes of other fungi, among which we have included species of importance in basic and medical research, and in biotechnology. The manually annotated kinomes of C. elegans
, D. discoideum
, D. melanogaster
, H. sapiens
and M. musculus
, as provided in Kinbase (http://www.kinase.com/kinbase/
), have also been included in the Kinomer v. 1.0 database. These will facilitate the manual annotation of other kinomes included in the database and which belong to the same taxonomic clade. The classification of a number of kinases in the kinomes of C. elegans
, D. discoideum
, D. melanogaster
, H. sapiens
and M. musculus
could be improved as suggested by the Kinomer v. 1.0 HMM group scores. However, careful manual annotation of the kinomes of other species in the same taxonomic clades will be performed in the future to make a more informed decision about the re-classification of such kinases.
To our knowledge, Kinomer v. 1.0 is unique in being based on a high-accuracy validated kinase-group classification method (6
). Other databases of protein kinases exist, but none of these offer the combination of breadth and accuracy of kinase classification that is present in Kinomer v. 1.0. These include KinMutBase (66
), a database of clinically validated mutations in human kinases that lead to disease, and RTK.db (67
), a database of receptor tyrosine kinases. The Protein Kinase Resource (68
) collates data from several databases and includes a subset of protein kinase 3D structures to produce high-quality multiple structure-based alignments. Kinbase (http://www.kinase.com/kinbase/
) contains manually curated kinomes classified according to the Hanks and Hunter classification of protein kinases (4
). Although of high quality, Kinbase only contains kinomes for nine species. Finally, KinG (69
) includes protein kinases identified in completed genomes that have been classified by a variety of metazoan kinome-based sequence search methods, but do not provide the confidence in kinase classification that is seen in Kinomer v. 1.0. Different eukaryotic lineages possess lineage-specific kinase groups and families that are just beginning to be characterized and which constitute as much as 50% of their kinomes (17
). The applicability of the KinG approach to non-metazoan kinases needs further testing. A similar limitation is encountered by the PANTHER (70
) database. Although not specific to protein kinases, PANTHER provides an extensive and detailed HMM library for kinase families and sub-families. These family and sub-family HMM libraries are trained on metazoan sequences and thus preclude their use to annotate non-metazoan sequences confidently into kinase families and sub-families which may not exist in non-metazoan species. Kinomer v. 1.0 annotates to the group level only and in our view annotating to the family/sub-family level requires manual curation.
In summary, Kinomer v. 1.0 is an easy-to-use interface to a novel database of both manually and automatically annotated kinomes. The availability of 43 eukaryotic kinomes in a relational database allows the easy querying of protein kinases by species and/or protein kinase group. In addition, the Kinomer v. 1.0 website includes a web server interface to the previously validated HMM library for the classification of peptide sequences into protein kinase groups. In the future, Kinomer v. 1.0 will be enhanced with the addition of a number of manually annotated kinomes of fungal, metazoan and photosynthetic organisms (Miranda-Saavedra, D., et al., manuscript in preparation). These will include the kinomes of pathogenic fungi of the Rhizopus and Fusarium geni, and the kinomes of several unicellular and multicellular photosynthetic organisms including diatoms, red, brown and green algae, and vascular plants. Thus, Kinomer v. 1.0 is a useful and developing repository of expert and automatically annotated kinomes.