BACKGROUND
the auroras are a conserved family of serine/threonine kinases which have essential functions in cell division  <cit> .
in mitosis, aurora kinases are required for chromosome segregation, condensation and orientation in the metaphase plate, spindle assembly, and the completion of cytokinesis.
model organism studies have played a pivotal role in functional characterization of aurora kinases.
aurora kinases were first identified as mutant alleles in drosophila melanogaster  that caused defective spindle-pole formation  <cit> .
subsequently, drosophila was found to have a second aurora homolog  <cit> , and the nematode, caenorhabditis elegans, similarly has two aurora-like genes  <cit> .
the fungi, saccharomyces cerevisiae and schizosaccharomyces pombe, have a single aurora, known as increase-in-ploidy  <dig>   <cit>  and aurora-related kinase  <dig>   <cit> , respectively.
among cold-blooded vertebrates, aurora kinases have been most widely studied in the frog, xenopus laevis, which has two kinases; aurora-a and aurora-b  <cit> .
more recently discovered is a third aurora kinase called aurora-c in rodents and humans  <cit> .
the aurora kinases are mitotic kinases that generally associate with chromosomes, often in complexes with other proteins, and interact with cytoskeletal components in cell division.
the three mammalian aurora kinases appear at specific locations during mitosis.
aurora-a, the "polar kinase", primarily associates with the separating centrosomes while aurora-b, the "equatorial kinase", is a chromosomal passenger protein  <cit> .
the least studied aurora kinase, aurora-c, appears to be localized to the centrosome from anaphase to telophase and is highly expressed in the testis  <cit> .
recent studies indicate that all three aurora kinases have strong associations with cancer.
aurora-a has been mapped to a region in the human chromosome  that is amplified in cancer cell lines and primary tumors  <cit> .
transfected mouse cell lines with aurora-a have been shown to cause tumors when injected into nude mice  <cit>  and a polymorphic variant  has been associated with human colon tumors  <cit> .
expression levels of aurora-b  <cit>  and aurora-c  <cit>  were elevated in several cancer cell lines relative to normal fibroblasts.
aurora-c is located on chromosome 19q <dig>  to  <dig> , a region associated with loss of heterozygosity in ovarian cancer  <cit>  and pancreatic carcinomas  <cit> .
thus, the inhibition of one or more aurora kinases might be a novel chemotherapeutic strategy against cancer  <cit> .
recently, several reports by research groups in pharmaceutical and biotechnology companies describe small molecules that target the atp-binding domain of aurora kinases, and have effects in human tumor cell lines  <cit> .
despite the importance of model organisms in understanding aurora kinase function, the evolutionary relationships among these variants are unclear.
two previous phylogenetic analyses of aurora kinases were incomplete because the contemporary complement of aurora kinases was unavailable  <cit>  or certain family members, namely the aurora-c kinases, were excluded  <cit> .
here, we present an evolutionary analysis of all known aurora kinases.
we show that vertebrate aurora kinases evolved through a series of gene duplication events from a chordate ancestor, and that they are highly distinct from invertebrate homologs.
moreover, the recent divergence, thus high level of sequence similarity, of human aurora-b and aurora-c suggests a novel anti-cancer strategy which might simultaneously target the atp-binding domains of this kinase pair with dual action inhibitors.
RESULTS
aurora evolution in chordates
in order to construct a comprehensive phylogenetic tree, genbank was searched for all possible aurora kinases.
in addition to previously published aurora kinase sequences, further chordate and urochordate aurora homologs were found by using mammalian aurora-a, aurora-b and aurora-c protein sequences as queries in blastp or tblastn  <cit>  searches of the genomes of the pufferfish, takifugu rubripes  <cit> , the zebrafish, danio rerio  <cit> , and the ascidian, ciona intestinalis  <cit> .
multiple sequence alignments show that the aurora kinase family is highly conserved among species .
pairwise sequence comparisons estimate that the mean proportion of similar amino acids  is much higher among all the different families of aurora-a, aurora-b and aurora-c of vertebrates  than within the same family  between vertebrates and invertebrates species .
this would suggest a recent evolutionary radiation of aurora families within vertebrates.
phylogenetic trees constructed using four methodologies, all rooted using polo-like kinases type  <dig> , show that all vertebrate auroras form a clade distinct from those of invertebrates .
the phylogenetic tree constructed by the neighbour-joining distance method shows moderate boot-strap support  for the evolution of all vertebrate auroras from a urochordate ancestor, represented by the ascidian, c. intestinalis.
the use of alternative kinase families, other than plk <dig>  to root the tree did not alter the internal topology of the aurora clade.
although its genome sequence is incomplete, c. intestinalis likely has only a single aurora homolog since other probable kinase open reading frames associated with the next top five blastp  <cit>  hits did not cluster with auroras from other species in phylogenetic trees.
among true vertebrates, our phylogenetic tree shows that the aurora kinases underwent two major gene duplication events.
the first split in cold-blooded vertebrates lead to the formation of two aurora subfamilies.
one branch encompasses all known vertebrate aurora-a sequences in a single orthologous lineage that includes fishes, amphibians and mammals.
this family includes previously identified aurora-a kinases in xenopus laevis, rodents and humans as well as a new putative ortholog in t. rubripes.
the second family, previously known as aurora-b  <cit>  consists of cold-blooded vertebrate and mammalian aurora-b as well as mammalian aurora-c. mammalian aurora-b and aurora-c are similarly related to the cold-blooded vertebrate aurora presently known as "aurora-b" in amphibians  and fish .
searches of t. rubripes and d. rerio protein and dna sequence databases detected several other putative serine/threonine kinase homologs but none were auroras according to phylogenetic analyses.
thus, cold-blooded vertebrates appear to have only a single aurora-a ortholog, a single aurora-b-like homolog, and lack an aurora-c ortholog.
conversely, aurora-a, aurora-b and aurora-c appear to be ubiquitous to mammals  where they are encoded by separate chromosomal loci.
it would appear that mammalian aurora-b and aurora-c evolved from a duplication event involving the ancestral aurora-b found in cold-blooded vertebrates.
this depiction of the evolutionary relationships of vertebrate auroras was consistently determined by four different phylogenetic methods with high bootstrap or bayesian posterior probability values .
comparisons of human aurora-b and aurora-c sequences to the resolved 3d structure of human aurora-a  <cit>  lends further support to the evolutionary scenario that vertebrate aurora-b and aurora-c are closely related paralogs .
of the  <dig> residues lining the atp-binding active site, only three vary among the different human aurora kinases; leu <dig>  thr <dig> and r <dig> , and all of these variants were specific to aurora-a .
aurora-b and aurora-c did not vary in their active site residues.
furthermore, all three auroras have a carboxy-terminal destruction box  but only aurora-a has the necessary amino-terminal a-box  for its functional activation  <cit> .
collectively, these comparisons of structure and motifs support the phylogeny depicting an early divergence of aurora-a from an aurora-b / aurora-c clade.
non-chordate evolution
the aurora kinases of plants and invertebrates are all outgroup lineages to chordates / urochordates .
although all phylogenetic methods strongly support the monophyly of chordate aurora kinases, the exact ordering among nodes leading to the various plant and invertebrate clusters were not resolved with similarly high bootstrap or probability values.
placement of plant aurora kinases between chordates and invertebrates might be an artifact of tree construction methods.
the earliest lineages of the aurora tree are those fungal model organisms with a single aurora-like homolog s. cerevisiae  and s. pombe .
other basal branches are the amitochondrial fungi, encephalitozoon cuniculi, and the kinetoplast protist, leishmania major  <cit> .
invertebrate aurora kinases, including those of the model organisms c. elegans and d. melanogaster, occupy separate early branches and are not, as their current names suggest, orthologs to either aurora-a or aurora-b of vertebrates.
an unrooted phylogenetic tree with only model organism species shows the same topology of vertebrate auroras as the more species-rich tree rooted by plk <dig> kinases .
however, similar kinases from c. elegans and d. melanogaster now cluster together.
the unrooted tree suggests that the invertebrate aurora-b kinase family evolved prior to the invertebrate aurora-a kinase family although further examples from other species are desirable to confirm this hypothesis.
the consensus scenario in both rooted and unrooted trees is that vertebrate aurora kinases are paralogous, rather than orthologous, to their invertebrate counterparts.
model organisms in context
aurora-b and aurora-c, as specific innovations in mammals, might have distinct protein-binding partners and cellular functions from those of aurora-b kinases in amphibians.
the perturbation of aurora-b function in different systems suggests variable kinetochore-microtubule interactions  <cit> .
transfection of normal rat kidney cells with a kinase-inactive, dominant negative form of aurora-b caused multiple defects in mitosis  <cit>  while an aurora-b kinase inactivating antibody seemed to have milder effects in xenopus tissue culture cells  <cit> .
xenopus aurora-a functions in the extrusion of the first polar body  <cit>  while in c. elegans aurora b plays a similar role  <cit> .
also, c. elegans aurora-b binds to a protein csc- <dig> which has no homolog in other studied systems  <cit> .
while these studies used different experimental methods, the lack of direct orthology among vertebrate and invertebrate aurora-a and aurora-b might also account for functional differences in these systems.
the evolutionary analysis presented here also suggests revisiting the present aurora nomenclature.
adams et al.
<cit>  proposed a naming scheme where, irrespective of species, the original aurora is known as aurora-a , followed by aurora-b  and aurora-c .
however, the proposed nomenclature fails to reflect evolutionary, and possibly functional, relationships among the auroras.
we suggest that aurora-a be retained as the name for all orthologs in mammals and cold-blooded vertebrates.
while aurora-b and aurora-c seem appropriate for mammalian versions, the ancestral cold-blooded vertebrate "aurora-b" might be renamed "aurora-bc".
as for invertebrates, the so-called aurora-a or aurora-b genes are clearly not orthologs to their respective vertebrate counterparts.
however, introducing a new nomenclature here might simply add further confusion to the field.
evolution of an anti-cancer target
there have been several recent reports of aurora kinase inhibitors that are under development by pharmaceutical or biotechnology companies for cancer treatment.
the compounds hesperadin  and zm <dig>  are suggested to be targeted to aurora-b.
while both studies show lesser levels of compound inhibition of aurora-a as well as several other kinases, neither report included aurora-c in their kinase profile.
selective inactivation of multiple kinases is not an undesirable pharmaceutical profile for a small molecule inhibitor and, in fact, could be the best strategy to achieve maximal clinical efficacy of an anti-cancer agent  <cit> .
indeed, an intense area of anti-cancer research is the development of small molecular atp analogues that generally target the kinase domain of protein kinases  <cit> .
for example, gleevec  for chronic myelogenous leukemia, is a small-molecule inhibitor that targets bcr-abl, c-kit and platelet-derived growth factor receptor kinases  <cit> .
recently, a selective inhibitor of all three aurora kinases, vx- <dig> , was reported to inhibit cell-cycle progression and induce apoptosis in various human tumor cell types and in vivo xenograft models  <cit> .
interestingly, although vx- <dig> is a potent inhibitor of all three aurora kinases, its apparent inhibition constant is much lower for aurora-a  than for either aurora-b  or aurora-c .
again, the compound's greater affinity for aurora-a, relative to aurora-b and aurora-c is compatible with the proposed evolutionary scenario of mammalian auroras.
CONCLUSIONS
evolutionary analysis shows that cell division aurora kinases, while consistent in theme throughout eukaryotes, have undergone lineage-specific expansions and specialization in metazoans.
aurora-c is the least known of the aurora kinases.
yet as an evolutionary innovation in mammals, further studies are very much warranted from the perspectives of better understanding its potential roles in both cell replication and tumor progression.
a better functional understanding of aurora-c would help clarify the evolutionary relationships of aurora-b and aurora-c in mammals relative to the ancestral aurora-bc in cold-blooded vertebrates.
additionally, the close evolutionary and structural relationships between mammalian aurora-b and aurora-c offers the tantalizing opportunity to design dual kinase inhibitors that might circumvent potential tumor cell resistance to mono-target chemotherapeutics.

 the auroras are a conserved family of serine/threonine kinases which have essential functions in cell division. in mitosis, aurora kinases are required for chromosome segregation, condensation and orientation in the metaphase plate, spindle assembly, and the completion of cytokinesis. model organism studies have played a pivotal role in functional characterization of aurora kinases. aurora kinases were first identified as mutant alleles in drosophila melanogaster that caused defective spindle-pole formation. subsequently, drosophila was found to have a second aurora homolog, and the nematode, caenorhabditis elegans, similarly has two aurora-like genes. the fungi, saccharomyces cerevisiae and schizosaccharomyces pombe, have a single aurora, known as increase-in-ploidy and aurora-related kinase, respectively. among cold-blooded vertebrates, aurora kinases have been most widely studied in the frog, xenopus laevis, which has two kinases; aurora-a and aurora-b. more recently discovered is a third aurora kinase called aurora-c in rodents and humans. the aurora kinases are mitotic kinases that generally associate with chromosomes, often in complexes with other proteins, and interact with cytoskeletal components in cell division. the three mammalian aurora kinases appear at specific locations during mitosis. aurora-a, the "polar kinase", primarily associates with the separating centrosomes while aurora-b, the "equatorial kinase", is a chromosomal passenger protein. the least studied aurora kinase, aurora-c, appears to be localized to the centrosome from anaphase to telophase and is highly expressed in the testis. recent studies indicate that all three aurora kinases have strong associations with cancer. aurora-a has been mapped to a region in the human chromosome that is amplified in cancer cell lines and primary tumors. transfected mouse cell lines with aurora-a have been shown to cause tumors when injected into nude mice and a polymorphic variant has been associated with human colon tumors. expression levels of aurora-b and aurora-c were elevated in several cancer cell lines relative to normal fibroblasts. aurora-c is located on chromosome 19q to, a region associated with loss of heterozygosity in ovarian cancer and pancreatic carcinomas. thus, the inhibition of one or more aurora kinases might be a novel chemotherapeutic strategy against cancer. recently, several reports by research groups in pharmaceutical and biotechnology companies describe small molecules that target the atp-binding domain of aurora kinases, and have effects in human tumor cell lines. despite the importance of model organisms in understanding aurora kinase function, the evolutionary relationships among these variants are unclear. two previous phylogenetic analyses of aurora kinases were incomplete because the contemporary complement of aurora kinases was unavailable or certain family members, namely the aurora-c kinases, were excluded. here, we present an evolutionary analysis of all known aurora kinases. we show that vertebrate aurora kinases evolved through a series of gene duplication events from a chordate ancestor, and that they are highly distinct from invertebrate homologs. moreover, the recent divergence, thus high level of sequence similarity, of human aurora-b and aurora-c suggests a novel anti-cancer strategy which might simultaneously target the atp-binding domains of this kinase pair with dual action inhibitors.  aurora evolution in chordates in order to construct a comprehensive phylogenetic tree, genbank was searched for all possible aurora kinases. in addition to previously published aurora kinase sequences, further chordate and urochordate aurora homologs were found by using mammalian aurora-a, aurora-b and aurora-c protein sequences as queries in blastp or tblastn searches of the genomes of the pufferfish, takifugu rubripes, the zebrafish, danio rerio, and the ascidian, ciona intestinalis. multiple sequence alignments show that the aurora kinase family is highly conserved among species. pairwise sequence comparisons estimate that the mean proportion of similar amino acids is much higher among all the different families of aurora-a, aurora-b and aurora-c of vertebrates than within the same family between vertebrates and invertebrates species. this would suggest a recent evolutionary radiation of aurora families within vertebrates. phylogenetic trees constructed using four methodologies, all rooted using polo-like kinases type, show that all vertebrate auroras form a clade distinct from those of invertebrates. the phylogenetic tree constructed by the neighbour-joining distance method shows moderate boot-strap support for the evolution of all vertebrate auroras from a urochordate ancestor, represented by the ascidian, c. intestinalis. the use of alternative kinase families, other than plk to root the tree did not alter the internal topology of the aurora clade. although its genome sequence is incomplete, c. intestinalis likely has only a single aurora homolog since other probable kinase open reading frames associated with the next top five blastp hits did not cluster with auroras from other species in phylogenetic trees. among true vertebrates, our phylogenetic tree shows that the aurora kinases underwent two major gene duplication events. the first split in cold-blooded vertebrates lead to the formation of two aurora subfamilies. one branch encompasses all known vertebrate aurora-a sequences in a single orthologous lineage that includes fishes, amphibians and mammals. this family includes previously identified aurora-a kinases in xenopus laevis, rodents and humans as well as a new putative ortholog in t. rubripes. the second family, previously known as aurora-b consists of cold-blooded vertebrate and mammalian aurora-b as well as mammalian aurora-c. mammalian aurora-b and aurora-c are similarly related to the cold-blooded vertebrate aurora presently known as "aurora-b" in amphibians and fish. searches of t. rubripes and d. rerio protein and dna sequence databases detected several other putative serine/threonine kinase homologs but none were auroras according to phylogenetic analyses. thus, cold-blooded vertebrates appear to have only a single aurora-a ortholog, a single aurora-b-like homolog, and lack an aurora-c ortholog. conversely, aurora-a, aurora-b and aurora-c appear to be ubiquitous to mammals where they are encoded by separate chromosomal loci. it would appear that mammalian aurora-b and aurora-c evolved from a duplication event involving the ancestral aurora-b found in cold-blooded vertebrates. this depiction of the evolutionary relationships of vertebrate auroras was consistently determined by four different phylogenetic methods with high bootstrap or bayesian posterior probability values. comparisons of human aurora-b and aurora-c sequences to the resolved 3d structure of human aurora-a lends further support to the evolutionary scenario that vertebrate aurora-b and aurora-c are closely related paralogs. of the residues lining the atp-binding active site, only three vary among the different human aurora kinases; leu thr and r, and all of these variants were specific to aurora-a. aurora-b and aurora-c did not vary in their active site residues. furthermore, all three auroras have a carboxy-terminal destruction box but only aurora-a has the necessary amino-terminal a-box for its functional activation. collectively, these comparisons of structure and motifs support the phylogeny depicting an early divergence of aurora-a from an aurora-b / aurora-c clade. non-chordate evolution the aurora kinases of plants and invertebrates are all outgroup lineages to chordates / urochordates. although all phylogenetic methods strongly support the monophyly of chordate aurora kinases, the exact ordering among nodes leading to the various plant and invertebrate clusters were not resolved with similarly high bootstrap or probability values. placement of plant aurora kinases between chordates and invertebrates might be an artifact of tree construction methods. the earliest lineages of the aurora tree are those fungal model organisms with a single aurora-like homolog s. cerevisiae and s. pombe. other basal branches are the amitochondrial fungi, encephalitozoon cuniculi, and the kinetoplast protist, leishmania major. invertebrate aurora kinases, including those of the model organisms c. elegans and d. melanogaster, occupy separate early branches and are not, as their current names suggest, orthologs to either aurora-a or aurora-b of vertebrates. an unrooted phylogenetic tree with only model organism species shows the same topology of vertebrate auroras as the more species-rich tree rooted by plk kinases. however, similar kinases from c. elegans and d. melanogaster now cluster together. the unrooted tree suggests that the invertebrate aurora-b kinase family evolved prior to the invertebrate aurora-a kinase family although further examples from other species are desirable to confirm this hypothesis. the consensus scenario in both rooted and unrooted trees is that vertebrate aurora kinases are paralogous, rather than orthologous, to their invertebrate counterparts. model organisms in context aurora-b and aurora-c, as specific innovations in mammals, might have distinct protein-binding partners and cellular functions from those of aurora-b kinases in amphibians. the perturbation of aurora-b function in different systems suggests variable kinetochore-microtubule interactions. transfection of normal rat kidney cells with a kinase-inactive, dominant negative form of aurora-b caused multiple defects in mitosis while an aurora-b kinase inactivating antibody seemed to have milder effects in xenopus tissue culture cells. xenopus aurora-a functions in the extrusion of the first polar body while in c. elegans aurora b plays a similar role. also, c. elegans aurora-b binds to a protein csc- which has no homolog in other studied systems. while these studies used different experimental methods, the lack of direct orthology among vertebrate and invertebrate aurora-a and aurora-b might also account for functional differences in these systems. the evolutionary analysis presented here also suggests revisiting the present aurora nomenclature. adams et al. proposed a naming scheme where, irrespective of species, the original aurora is known as aurora-a, followed by aurora-b and aurora-c. however, the proposed nomenclature fails to reflect evolutionary, and possibly functional, relationships among the auroras. we suggest that aurora-a be retained as the name for all orthologs in mammals and cold-blooded vertebrates. while aurora-b and aurora-c seem appropriate for mammalian versions, the ancestral cold-blooded vertebrate "aurora-b" might be renamed "aurora-bc". as for invertebrates, the so-called aurora-a or aurora-b genes are clearly not orthologs to their respective vertebrate counterparts. however, introducing a new nomenclature here might simply add further confusion to the field. evolution of an anti-cancer target there have been several recent reports of aurora kinase inhibitors that are under development by pharmaceutical or biotechnology companies for cancer treatment. the compounds hesperadin and zm are suggested to be targeted to aurora-b. while both studies show lesser levels of compound inhibition of aurora-a as well as several other kinases, neither report included aurora-c in their kinase profile. selective inactivation of multiple kinases is not an undesirable pharmaceutical profile for a small molecule inhibitor and, in fact, could be the best strategy to achieve maximal clinical efficacy of an anti-cancer agent. indeed, an intense area of anti-cancer research is the development of small molecular atp analogues that generally target the kinase domain of protein kinases. for example, gleevec for chronic myelogenous leukemia, is a small-molecule inhibitor that targets bcr-abl, c-kit and platelet-derived growth factor receptor kinases. recently, a selective inhibitor of all three aurora kinases, vx-, was reported to inhibit cell-cycle progression and induce apoptosis in various human tumor cell types and in vivo xenograft models. interestingly, although vx- is a potent inhibitor of all three aurora kinases, its apparent inhibition constant is much lower for aurora-a than for either aurora-b or aurora-c. again, the compound's greater affinity for aurora-a, relative to aurora-b and aurora-c is compatible with the proposed evolutionary scenario of mammalian auroras.  evolutionary analysis shows that cell division aurora kinases, while consistent in theme throughout eukaryotes, have undergone lineage-specific expansions and specialization in metazoans. aurora-c is the least known of the aurora kinases. yet as an evolutionary innovation in mammals, further studies are very much warranted from the perspectives of better understanding its potential roles in both cell replication and tumor progression. a better functional understanding of aurora-c would help clarify the evolutionary relationships of aurora-b and aurora-c in mammals relative to the ancestral aurora-bc in cold-blooded vertebrates. additionally, the close evolutionary and structural relationships between mammalian aurora-b and aurora-c offers the tantalizing opportunity to design dual kinase inhibitors that might circumvent potential tumor cell resistance to mono-target chemotherapeutics. 
abnormalities in aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the atp-binding domain of these kinases. mammals uniquely have three aurora kinases, aurora-a, aurora-b, and aurora-c, while for other metazoans, including the frog, fruitfly and nematode, only aurora-a and aurora-b kinases are known. based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of aurora kinases. in addition, given the important role of aurora kinases in cancer, evolutionary analysis and comparisons of atp-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both aurora-b and aurora-c kinases. of the residues lining the atp-binding active site, only three were variant and all were specific to aurora-a. comparisons of human aurora-b and aurora-c sequences to the resolved 3d structure of human aurora-a lends further support to the evolutionary scenario that vertebrate aurora-b and aurora-c are closely related paralogs. phylogenetic trees suggest that all three vertebrate auroras evolved from a single urochordate ancestor. these findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. as key regulators of mitotic chromosome segregation, the aurora family of serine/threonine kinases play an important role in cell division. in this study, we found that invertebrate aurora-a and aurora-b kinases are highly divergent protein families from their chordate counterparts. from an evolutionary perspective, the species distribution of the aurora kinase family is complex. here, we present comprehensive evolutionary analyses of the aurora kinase family. all so-called aurora-a and aurora-b kinases of non-chordates are ancestral to the clade of chordate auroras and, therefore, are not strictly orthologous to vertebrate counterparts. specifically, aurora-a is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar aurora-b and aurora-c evolved more recently in mammals from a duplication of an ancestral aurora-b/c gene found in cold-blooded vertebrates.
 as key regulators of mitotic chromosome segregation, the aurora family of serine/threonine kinases play an important role in cell division. abnormalities in aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the atp-binding domain of these kinases. from an evolutionary perspective, the species distribution of the aurora kinase family is complex. mammals uniquely have three aurora kinases, aurora-a, aurora-b, and aurora-c, while for other metazoans, including the frog, fruitfly and nematode, only aurora-a and aurora-b kinases are known. the fungi have a single aurora-like homolog. based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of aurora kinases. however, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. here, we present comprehensive evolutionary analyses of the aurora kinase family.  phylogenetic trees suggest that all three vertebrate auroras evolved from a single urochordate ancestor. specifically, aurora-a is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar aurora-b and aurora-c evolved more recently in mammals from a duplication of an ancestral aurora-b/c gene found in cold-blooded vertebrates. all so-called aurora-a and aurora-b kinases of non-chordates are ancestral to the clade of chordate auroras and, therefore, are not strictly orthologous to vertebrate counterparts. comparisons of human aurora-b and aurora-c sequences to the resolved 3d structure of human aurora-a lends further support to the evolutionary scenario that vertebrate aurora-b and aurora-c are closely related paralogs. of the residues lining the atp-binding active site, only three were variant and all were specific to aurora-a.  in this study, we found that invertebrate aurora-a and aurora-b kinases are highly divergent protein families from their chordate counterparts. furthermore, while the aurora-a family is ubiquitous among all vertebrates, the aurora-b and aurora-c families in humans arose from a gene duplication event in mammals. these findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. in addition, given the important role of aurora kinases in cancer, evolutionary analysis and comparisons of atp-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both aurora-b and aurora-c kinases. 