blood flukes of the genus schistosoma ( platyhelminthes : trematoda ) are the causative agents of schistosomiasis living in the bloodstream of their final hosts . over 200 million people are infected worldwide and about 700 million live in endemic regions , with more than 90% of the cases of infection occurring in sub - saharan africa [ 1 , 2 ] . schistosomes have a complex developmental cycle with diverse life stages remarkably well adapted to their environment and hosts . such a successful and prolific schistosome life cycle has been shown to be dependent on the adaptive molecular  dialogue  that takes place between the parasite and the host . the contact of the parasite with host signals ( e.g. , hormones , growth factors , etc . ) could control cell proliferation and differentiation processes in schistosomes . in this context , diverse molecular pathways dependent on kinase - mediated signaling have been described in schistosomes and shown to be involved in host - parasite relationships . the molecular phylogeny of the protein kinases upon which kinbase was developed   was first described by hanks et al . . in this classification scheme , the protein kinase superfamily is split into two groups : eukaryotic protein kinases ( epks ) and atypical protein kinases ( apks ) . the former constitutes one of the largest and most important protein families in eukaryotes , accounting for ~2% of the total proteins identified in a variety of genomes . the epks are further divided into nine groups ( tk , agc , camk , cmgc , ck1 , ste , rgc , tkl , and other ) based on sequence similarity of their catalytic domains , the presence of accessory domains , and their modes of regulation . 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 coordination of complex pathways . many of these pathways are highly conserved among eukaryotes with 53 distinct kinase functions , which are conserved among yeasts , nematodes , insects , and vertebrates . multicellular life demands complex activities such as cell proliferation , differentiation , adhesion , and motility to be precisely controlled . many of these processes are in fact regulated by protein tyrosine kinases ( tks ) . the tyrosine phosphorylation occurs via the covalent addition of a phosphate group from atp or gtp to tyrosine residues in a variety of proteins , and the emergence of this signaling mechanism was likely a key enabling event in the transition to multicellularity . the tyrosine kinase comprises cell surface receptor ( rtk ) and nonreceptor or cytosolic ( ctk ) kinases , classified into 29 families ( table 1 ) . deregulation of the tyrosine kinase activity by various mechanisms leading to gain or loss of function have been observed in a large number of tyrosine kinases and shown to be associated with different human diseases . due to their central regulatory roles , tyrosine kinases are considered interesting targets for the treatment of various diseases , most prominently cancer . recently , the draft genome of s. mansoni was published   and large - scale transcriptome projects have provided detailed information for the identification of protein kinases . the epk complement of s. mansoni , defined as the epkinome , consists of 252 epks in the predicted proteome , representing 1.9% of the total proteins encoded the parasite genome . only 16 s. mansoni epks were experimentally studied , with 10 belonging to the tk group [ 16 , 17 ] . the tyrosine kinases represent the fourth largest group of the s. mansoni epkinome including 15  rtks and 19  ctks , classified into 18 families . of the parasite rtks , 10 have homologs in six distinct human protein families , two belong to venus kinase receptor family [ 18 , 19 ] , also present in many insects , and three were not grouped into families previously described in metazoans . at the moment , several tyrosine kinases characterized in s. mansoni are described as potential targets for therapy against schistosomiasis . tyrosine kinases constitute the largest group of epks in caenorhabditis elegans , with 92 members , which represent 21% of all epks encoded in the nematode genome . in c. elegans , these proteins correspond to 40  rtks and 52 ctks . the rtks include 16 members of the worm - specific kin-15-family , 13  rtks with orthologs representing 10 of the 20 families of human rtks , and 11  rtks that remain unclassified with no identifiable mammalian counterpart . the fer family is the largest in c. elegans , with 37 members . only a single member , smfes , furthermore , immunolocalization assays showed that smfes is particularly expressed at the terebratorium of miracidia , an organ that helps the penetration of the parasite in the snail host , and tegument of cercaria and schistosomula skin stage . these findings suggest that smfes may play a role in signal transduction pathways involved in larval transformation after penetration into intermediate and definitive hosts [ 4 , 15 ] . ninety unique tyrosine kinase genes , representing ~17% of all epks , were identified in the human genome , along with nine pseudogenes [ 9 , 21 ] . there were 58 rtks distributed into 20 families and 32 ctks grouped into 10 families . humans contain 14 members of eph family , while only a single member ( smp_139480 ) was identified in s. mansoni ( table 2 ) . eph receptor signaling is responsible for the most diverse set of biological events performed by any tyrosine kinase including organ development , tissue remodeling , neuronal signaling and insulin secretion , and bone metabolism . here , we discuss the diversity of the s. mansoni tyrosine kinases from the functional and evolutionary perspectives . this review is organized in three main sections : phospho - tyrosine signaling network , tyrosine kinase functional diversification , and tyrosine kinases as new anti - schistosome drug targets . the cellular signaling machinery mediated by tyrosine kinases is widely studied in modern metazoans . in these organisms phosphotyrosine - signaling pathways are mediated by a  toolkit  of three functional protein domains ( figure 1 ) : the tyrosine kinase catalytic domain ( tk ) that phosphorylates - specific target tyrosine residues , the phosphotyrosine - phosphatase domain ( ptp ) that removes the phosphates , and the src homology 2 domain ( sh2 ) that recognize these modifications . together , these domains form the  writer ,   eraser ,  and  reader  domains that is common to many diverse cellular information processes . phosphotyrosine - binding ( ptb ) domains also participate in tyrosine kinase - signaling networks ( not included in figure 1 ) . according to the s. mansoni relational database , schistodb ( www.schistodb.net ) , there are two genes , smp_139400 and smp_126500 , that code for proteins with significant similarity to the ptb domain ( pf08416 ) as defined by the pfam database . the s. mansoni ptb domains are members of the tensin cytoplasmic phospho - protein ( tec ) family . ptb domains are underrepresented in the s. mansoni genome when compared to the 37 proteins with sh2 domains ( figure 1 ,  reader  ) . the remaining ones are tensin , suppressors of cytokine signaling , ty suppressors , rho gtpase , ras gtpase , and adaptor proteins . analysis of the c. elegans genome has indicated 11 ptb domain proteins related to the phosphotyrosine - binding activity . similar to s. mansoni , the ptb domain is relatively underrepresented when compared to the 57 proteins with sh2 domains encoded in the c. elegans genome . there are nearly 60 ptb domain proteins in humans , six of which have been reported to carry mutations that contribute to inherited human diseases such as familial stroke , hypercholesteremia , coronary artery disease , alzheimer 's disease , and diabetes . these findings demonstrated that these proteins play an important role in organizing signaling complexes in a broad range of physiological processes . ptb domains also bind head groups of acidic phospholipids consistent with the nearly exclusive subcellular localization of ptb domains to the membrane or juxtamembrane regions , suggesting that most ptb domains are multifunctional . similar to s. mansoni and c. elegans , the ptb domain is relatively underrepresented when compared to the 110 proteins with sh2 domains encoded in the human genome . the number of ptb domain proteins is greater in human than in s. mansoni and c. elegans proteomes . in addition , among the 946 ptb domain proteins deposited in smart , eight are found in echinoderms , 28 in nematodes , 58 in arthropods , and 852 in chordates . these data suggest higher levels of diversity of the vertebrate ptb domains in relation to invertebrates . searching the s. mansoni relational database , schistodb , for proteins with significant similarity to the tyrosine phosphatase sequence domain ( pf00102 ) ( figure 1 ,  eraser  ) as defined by finn et al . the number of tyrosine kinase encoding genes ( 34 proteins ) in the s. mansoni genome is higher than that of tyrosine phosphatases , which suggests that these enzymes may act on different substrates . however , we should consider the following observations : ( 1 ) among the 34 s. mansoni tyrosine kinases , four are predicted to be catalytically inactive , while the number of inactive tyrosine phosphatases is not known at the moment ; ( 2 ) there are eight genes encoding members of the dual specificity phosphatase family , which can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues within one substrate ; ( 3 ) the s. mansoni genomic data remains fragmented and much work is still necessary to complete the assembly of the genome sequences . therefore , the number of tyrosine phosphatases may be underestimated in the actual assembly and annotation of the s. mansoni genome . this coordinate expansion in the nematode lineage could possibly reflect the biological need to maintain a tight regulation of the phosphotyrosine process . the human genome encodes 107 tyrosine phosphatase family members , which together exceed the number tyrosine kinases in the same organism . however , a more detailed inspection reveals that only 81 proteins are active phosphatases with the ability to dephosphorylate phosphotyrosine residues . the remaining phosphatases are catalytically inactive ( 11 proteins ) , dephosphorylate mrnas ( two proteins ) , or dephosphorylate inositol phospholipids ( 13 proteins ) . out of the 90 human tyrosine kinases , 85 are believed to be catalytically active leading to similar numbers of active tyrosine phosphatases and kinases in humans . recently , the crucial role of tyrosine phosphorylation was shown in snail - schistosome interactions . the exposure of miracidia to the haemolymph of schistosome - susceptible snails is followed by increased protein tyrosine phosphorylation profile . in addition , the treatment of miracidia with a tyrosine kinase - specific inhibitor significantly impaired their development into primary sporocysts . these results suggest the participation of signal transduction pathways mediated by tyrosine kinases during the snail - host infection and transformation of the evolutionary stages of the s. mansoni life cycle . schistosoma proteins smtk3 ( smp_054500 ) and smtk5 ( smp_136300 ) are src family members , while smtk4 ( smp_149460 ) belongs to the syk family . the later is present in reproductive organs and it is possibly involved in the development of gonads and oogenesis [ 36 , 37 ] . detailed knowledge of the signaling pathways that control schistosome growth , metabolism , differentiation and survival is of particular interest because only mature adult worms produce eggs , which are responsible for disease pathology . a simple way to assess molecular diversity of gene / protein families is to analyze their domain organization [ 38 , 39 ] . the functional diversity of the s. mansoni tyrosine kinases is reflected by the presence of 14 distinct accessory domains besides the catalytic domain that is found in all epks ( figure 2 ) . following the tyrosine kinase catalytic domain , the two most frequently occurring protein domains in the s. mansoni tyrosine kinases are src homology 2 ( sh2 ) and src homology 3 ( sh3 ) domains . important clues regarding the relationships between sh2 and sh3 domains are provided by the genomes of unicellular eukaryotes , which lack the complete set of phosphotyrosine signaling machinery . the genome of a simple unicellular eukaryote like the budding yeast , saccharomyces cerevisiae shows one proto - sh2 domain , which shares similarity with the sh2 domain from other organisms but , does not show the phosphotyrosine - binding activity . although sh2 is not present in prokaryotes , a variety of sh2-containing tyrosine kinases have been found in organisms , such as the sponge , implying that many of the domain rearrangements happened early in metazoan evolution . tyrosine phosphorylation mediates the formation of heteromeric protein complexes at or near the plasma membrane by acting as a  switch  to induce the sh2 domain binding as described elsewhere . the formation of these protein complexes , on the other hand , is likely to control the activation of signal transduction pathways by tyrosine kinases . thus , the sh2 domain serves as the prototype for a growing family of protein - interaction domains , characteristic of polypeptides involved in signal transduction pathways . together with the sh2 domain , the sh3 may modulate interactions with the cytoskeleton and membrane . the sh2 domain is present in eight s. mansoni tyrosine kinases grouped into four ctk families : csk , fer , scr , syk , and tec ( figure 2 ) . members of scr and syk families have been characterized and are involved in organizing the cytoskeleton in the parasite gonads   and germ cell development . the six sh3-containing domain tyrosine kinases in s. mansoni are present in three ctk families : csk , syk , and tec ( figure 2 ) . members of csk and syk families have the sh3 domain in addition to sh2 and the tyrosine kinase catalytic domains . in addition to these domains , members of the tec family contain two other domains : bruton 's tyrosine kinase ( btk ) and pleckstrin homology ( ph ) domains . similar domain architecture is observed in the tec family of the choanoflagellate , monosiga brevicollis . currently , m. brevicollis is the only unicellular organism that presents a tyrosine kinase signalling network that has been either characterized experimentally or identified by computational prediction . an alternative way to investigate functional diversification of proteins and protein families is through phylogenomics (  intersection between phylogenetics and genomics  ) as previously proposed . this evolutionary framework , originally designed to improve functional prediction of uncharacterized genes / proteins , has been applied to a broad range of studies [ 43 , 44 ] . the relationships among 23 selected tyrosine kinases from s. mansoni were inferred by phylogenomic analysis of their catalytic domain sequence ( data not shown ) . tree information corroborates the grouping of these proteins into distinct families encoded in the parasite genome , such as egfr ( epidermal growth factor receptor ) and vkr ( venus flytrap kinase receptors ) . as mentioned before , most of these proteins remain experimentally uncharacterized . some of them are proposed as drug targets , that is , abl and egfr family members . the aforementioned approach could be used as a framework for hypothesis testing to gain insights into the changes leading to sequence and functional diversification across proteins / organisms over evolutionary time . in the past decades ,  a single drug for a single target  paradigm has dominated drug discovery approaches . a systems - biology approach , especially focused on the elucidation of cellular signaling pathways , could provide a framework , for anti - schistosome drug discovery . signaling pathways controlled by protein kinases are a central theme in biological systems . an aberrant protein kinase activity has been implicated in a variety of human diseases , such as cancer , rheumatoid arthritis , and cardiovascular and neurological disorders . the design and development of specific inhibitors for protein kinases , thus , became a major strategy in many drug discovery programs . when the focus is the discovery of new drugs against schistosomiasis it is necessary to answer some key questions : what is the current need for new drugs against schistosomiasis ? what are the challenges faced in the process of finding drugs ? what genes / proteins can be used as potential chemotherapeutic targets ? and finally , are tyrosine kinases potential targets for new drugs against schistosoma species ? the drug praziquantel ( pzq ) , for which the detailed mode of action is still unclear , is the only commercially available treatment for the schistosomiasis . pzq success as a drug has contributed to a lack of urgency and investment in identifying new therapies , either in terms of searching for chemical entities or molecular targets . however , resistance to pzq has been developed in more than one occasion in the laboratory , and the extensive use of pzq in mass drug administration programs has raised concern regarding the selection of drug resistant schistosomes in the field . there has been little incentive to invest in the discovery and development of antitrematode drugs . however , public - private partnerships have been formed for some of the neglected tropical diseases . one example of such partnership is the drugs for neglected diseases initiative ( dndi ) , focusing on human african trypanosomiasis and leishmaniasis . drug discovery and development programs do not yet exist for any of the major helminthoses such as schistosomiasis . by using a comparative chemogenomics approach , caffrey and colleagues have identified 72 potential target proteins in the s. mansoni predicted proteome . among the 72 proteins identified , furthermore , some anticancer drugs developed to inhibit deregulated protein kinases can also inhibit schistosome enzymes , thus blocking parasite development . polo kinases ( plks ) have crucial conserved functions in controlling the eukaryotic cell cycle through several events during mitosis using the specific inhibitor , bi 2536 , to block smplk1 kinase activity caused profound alterations in the gonads of both genders , including a reduction of gamete production . at present , the dihydropteridinone compound bi 2536 is the most potent and advanced anti - plk1 molecule in clinical trials . tyrphostins ag 538 and ag 1024   as well as hnmpa-(am ) 3   inhibit the tyrosine kinase of human insulin receptors and were shown to reduce glucose uptake in schistosomes . both the tgf-r tyrosine kinase inhibitor triki and the src - kinase inhibitor herbimycin a reduce mitotic activity and fecundity in schistosomes in an additive manner . h89 , an inhibitor of the catalytic unit of pka ( pka - c ) , induces loss of egg production and viability in schistosomes . piceatannol , an inhibitor of the syk tyrosine kinase , provokes reduction of egg production in treated schistosomes . imatinib , an abl kinase inhibitor , approved by the us food and drug administration ( fda ) and used in the clinic , has fatal physiological effects on schistosomes in vitro at doses similar to those used for cancer treatment in humans [ 51 , 58 ] . treatment with imatinib is generally well tolerated , even over a period of many years , with a low incidence of severe side - effects . the results obtained using anticancer drugs for treating schistosomiasis suggest that the treatment period using a kinase inhibitor with schistosome - killing properties will be significantly shorter compared to cancer treatment . however , three main points make it difficult to use kinase inhibitors as anti - schistosome compound when compared to pzq : ( 1 ) unlike most kinase inhibitors , pzq is generally well tolerated ; ( 2 ) pzq represents a low - cost medicine , whereas cancer drugs such as imatinib are still expensive , and ( 3 ) in particular , protein kinases share very similar structural and functional features , making it more difficult to design a specific inhibitor . issues regarding the enzyme specificity may be overcome by drug redesign guided by the identification of structural features that promote promiscuity and selectivity filters that enable target discrimination . furthermore , costs could be brought down via generic producers with expiring patents , which in the case of imatinib will happen soon . second - generation compounds for the same target are already in the pipeline , and this will have an additional effect on price reduction . the use of tk inhibitors as chemotherapeutic agents may be extended to other helminth parasites , including the filarial nematode brugia malayi . indeed , the genome of this parasite encodes a total of 205 protein kinases that are potential drug targets and correspond to about half of the human complement . tyrosine kinases have been shown to be essential for the proliferation and/or viability of clinically relevant schistosome life - cycle stages . moreover , the available data concerning the expression of tyrosine kinases throughout the life - cycle , which are accessible at schistodb , show that a number of these enzymes are expressed in schistosomula and/or adult worms , the therapeutic targets . serial analysis of gene expression ( sage ) data shows that 19 tyrosine kinases are expressed in adult worms ( table 3 ) . on the other hand , expressed sequence tag ( est ) suggests that 18 are expressed in adult worms , among which 11 are also expressed by 3-day old schistosomula and one by 7-day - old schistosomula . one ctk ( smp_134800 ) is expressed only in 7-day - old schistosomula ( table 3 ) . quantitative real - time pcr assays are also necessary to verify stage specificity of tyrosine kinases expression . however , tks expressed in common by adult worms and schistosomula should probably be preferentially targeted for drug discovery . therefore , tyrosine kinases inhibitors are applicable to the development of alternative strategies to reduce both pathology and transmission of schistosomiasis . schistosome studies have truly entered a new stage with the recent publication of the s. mansoni [ 13 , 62 ] and s. japonicum genomic sequence data . it is now vital to investigate the functional roles of gene products to answer questions concerning the fundamental biology of these important human parasites . as discussed here , tyrosine kinases , which participate in signaling pathways , are of interest when it comes to understand organisms such as parasites . multicellular organisms use a , three - protein domain ,  toolkit  to mediate phosphotyrosine signaling : tyrosine kinases catalytic (  writer  ) , tyrosine phosphatase catalytic (  eraser  ) , and src homology 2 (  reader  ) responsible for phosphotyrosine modifications of a variety of proteins . phosphotyrosine signaling is a complex system that exerts crucial biological effects by regulation of interactions at the molecular and physiological levels . the cck4 , fak , musk , syk , and tec tyrosine kinase families are found both in s. mansoni and in humans , but not in c. elegans ( table 2 ) . the vkr family is present neither in c. elegans nor in humans , nor in the model insect drosophila melanogaster . moreover , s. mansoni is the only organism so far discovered in which more than one representative of the vkr family is present . domain shuffling has been observed in several organisms leading to sequence , structural , and/or functional diversification of proteins . the functional diversity observed in the s. mansoni tyrosine kinases is reflected by the presence and distinct combinations of 14 accessory domains besides the catalytic domain , which is found in all epks described so far . s. mansoni has a complex life cycle ; therefore , acquiring proteins with new functions is essential for the evolution of the parasite . the dependence on a single drug , pzq , for treating schistosomiasis and the reports of possible resistance   motivates the search for new drug targets . the design and development of specific inhibitors for tyrosine kinases thus have became a major strategy in many drug discovery programs . tyrosine kinases have been shown to be essential for proliferation and/or viability of parasite life - cycle stages that are clinically relevant . therefore , tyrosine kinases inhibitors are applicable to the development of alternative strategies to reduce both pathology and transmission of schistosomiasis . combining computational and experimental approaches of other helminth parasites , whose genome sequencing projects are underway , should greatly advance our understanding on the functional diversity of tyrosine kinases and the parasite and on the parasite biology and evolution .
schistosoma mansoni , one of the causative agents of schistosomiasis , has a complex life cycle infecting over 200 million people worldwide . 
 such a successful and prolific parasite life cycle has been shown to be dependent on the adaptive interaction between the parasite and hosts . 
 tyrosine kinases ( tks ) play a key role in signaling pathways as demonstrated by a large body of experimental work in eukaryotes . 
 furthermore , comparative genomics have allowed the identification of tk homologs and provided insights into the functional role of tks in several biological systems . 
 finally , tk structural biology has provided a rational basis for obtaining selective inhibitors directed to the treatment of human diseases . 
 this paper covers the important aspects of the phospho - tyrosine signaling network in s. mansoni , caenorhabditis elegans , and humans , the main process of functional diversification of tks , that is , protein - domain shuffling , and also discusses tks as targets for the development of new anti - schistosome drugs .