BMC Genomics 2009, 10:622 http://www.biomedcentral.com/1471-2164/10/622 doFCigiafgfnreuitzroreoendnt1sdrpeolipcmreeavisnaernoitarangttaisonnieznaoctfiooddnoemdabiny oarsginangliezagteionne owf hniecwhlhyarveec- Cartoon representation of domain organization of newly recognized splice variants encoded by a single gene which have different domain organization. Splice variants shown in the figure are closely related to a) MARK kinase; b) CAMK II subfamily; c) Fyn tyrosine kinase d) Trio kinase. Abbreviations followed in the figure: UBA, Ubiquitin Associated Domain; KA1, Kinase Associated Domain 1; CAMKII_AD, Calcium/calmodulin dependent protein kinase II Association; SH3, Src homology 3; SH2, Src homology 2; I- set, Immunoglobulin domain; RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; PH, Pleck- strin Homology domain. (ENSP00000346671) encoded by the gene ENSG00000010810 lacks SH3 domain which is found tethered N-terminal to the Fyn tyrosine kinase (Figure 1C) which has role in increasing local concentration of pro- teins, altering their subcellular location and mediating the assembly of large multiprotein complexes. Interestingly, two splice variants (ENSP00000339291, ENSP00000339299) encoded by the gene ENSG00000038382 which belong to Trio subfamily of CAMK group regulated by calmodulin, may mediate apoptosis induced by interferon-gamma [36], have also different domain organizations. In this example one of the members (ENSP00000339299) has multiple domains like spectrin repeats, two copies of Rho GEF and PH domain, SH3 and I-set (Immunoglobulin) domains whereas another variant (ENSP00000339291) is lacking all these domains except I-set domain which is in the N- terminus of the kinase domain (Figure 1D). There are many more splice variants which are encoded by the same gene but lack one or more regulatory accessory domains and these are listed in Additional file 2. Additional file 2 also lists few examples of splice variants which are encoded by same gene but their catalytic kinase domain belong to different protein kinase subfamilies. For example from a set of six splice variants (ENSP00000320622, ENSP00000346846, ENSP000 00352088, ENSP00000353452, ENSP00000353530, ENSP00000355024) encoded by the gene ENSG00000065534 five splice variants belong to MLCK (Mixed Lineage Chain Kinase) subfamily whereas one of the splice variants belong to DRAK (death-associated pro- tein kinase [DAP-kinase]-related apoptosis-inducing kinase) subfamily which plays important roles in apop- totic signal transduction [37]. There is another example in which one of the four splice variants (ENSP 00000354170) encoded by ENSG00000068078 gene belong to Vascular Endothelial Growth Factor protein tyrosine kinase subfamily whereas other three (ENSP00000231803, ENSP00000260795, ENSP00 000339824) belong to Fibroblast growth factor receptor subfamily (Additional file 2). Expression of human kinases splice variants in different cell types Additional file 3 provides information on expression of many human kinase splice variants in different tissue or cell types. This information was obtained from ENSEMBL database. From this Table it can be observed that at least one splice variant product from each of 44 genes is expressed in two or more different tissues compared to other splice variants corresponding to the same gene. This number represents a proportion of ~49% of the genes implicated in variant splicing. In all such cases splice var- iants corresponding to a gene belong to the same kinase subfamily. For example, the gene ENSG00000141068 produces two kinases belonging to the same sub-family, one expressing in 4 tissues (ENSP00000323178) and the other expressing in 17 tissues (ENSP00000268763). Conclusions Remarkable improvement in the quality of human genomic data enabled us to generate a more comprehen- sive repertoire of human kinases with identification of 918 protein kinase gene products with many of these rep- resenting splice variants with altered properties. Previous analyses on human kinome [1-3] presented much smaller set of kinases as splice variants were not analyzed in these early papers. Indeed Milensi et al [11] extended the early analysis of human kinome considering splice variation and, in particular, reported 5 further kinase genes and a pseudogene. However, present study indicates that the alternative splice forms of protein kinase genes are far more abundant than previously thought and seems to provide interesting variety with implications in biological pathways and processes. Present analysis has unearthed newly recognized protein kinase splice variants with Page 4 of 7 (page number not for citation purposes)