Department of Biological Chemistry, UC Davis School of Medicine, UC Davis Cancer Center, Sacramento, California, CA 95817, USA

Correspondence to: D R Robinson, UC Davis Cancer Center, 4645 Second Ave., Sacramento, California, CA 95817, USA

As the sequencing of the human genome is completed by the Human Genome Project, the analysis of this rich source of information will illuminate many areas in medicine and biology. The protein tyrosine kinases are a large multigene family with particular relevance to many human diseases, including cancer. A search of the human genome for tyrosine kinase coding elements identified several novel genes and enabled the creation of a nonredundant catalog of tyrosine kinase genes. Ninety unique kinase genes can be identified in the human genome, along with five pseudogenes. Of the 90 tyrosine kinases, 58 are receptor type, distributed into 20 subfamilies. The 32 nonreceptor tyrosine kinases can be placed in 10 subfamilies. Additionally, mouse orthologs can be identified for nearly all the human tyrosine kinases. The completion of the human tyrosine kinase family tree provides a framework for further advances in biomedical science. Oncogene (2000) 19, 5548-5557.

tyrosine kinase; human genome; receptor; non-receptor; mouse; ortholog

Introduction

The protein tyrosine kinases (PTKs) are a large and diverse multigene family found only in Metazoans. Their principal functions involve the regulation of multicellular aspects of the organism. Cell to cell signals concerning growth, differentiation, adhesion, motility, and death, are frequently transmitted through tyrosine kinases. In contrast, many of the serine/threonine kinase families, such as cyclin dependent kinases and MAP kinases, are conserved throughout eukaryotes and regulate processes in both unicellular and multicellular organisms. In humans, tyrosine kinases have been demonstrated to play significant roles in the development of many disease states, including diabetes and cancer. Historically, tyrosine kinases define the prototypical class of oncogenes, involved in most forms of human malignancies. Tyrosine kinase genes have also been linked to a wide variety of congenital syndromes (Robertson et al., 2000). Intensive study of this relevant gene family over the past 20 years has produced numerous insights into the structure, regulation, and function of these genes and their products. Many excellent reviews of protein tyrosine kinase structure and function have been published recently and are listed in Table 1.

Tyrosine kinases contain highly conserved catalytic domains similar to those in protein serine/threonine and dual-specificity kinases but with unique subdomain motifs clearly identifying members as tyrosine kinases (Hanks and Quinn, 1991). The high degree of conservation of the tyrosine kinase motifs has allowed the identification of tyrosine kinase genes in most metazoan phyla. Tyrosine kinase genes have been characterized in poriferans, cnidarians, nematodes, annelids, arthropods, echinoderms, and chordates (Suga et al., 1999; Muller et al., 1999; Miller et al., 2000; Rikke et al., 2000; Lucini et al., 1999; Sakuma et al., 1997). These sequences provide an extensive set of probes to investigate the genomic sequences of other species. Protein kinase catalogs of Saccharomyces cerevesiae, Caenorhabditis elegans, and Drosophila melanogaster have been compiled from the completed genomic sequences of these organisms (Hunter and Plowman, 1997; Plowman et al., 1999; Popovici et al., 1999; Morrison et al., 2000). Thanks to the efforts of all involved in the Human Genome Project, the draft sequence of the euchromatic regions of the human genome is nearly complete, an achievement of immeasurable significance. The accessibility of this vast information to researchers in the biological sciences should greatly facilitate further advances. The large well-studied family of protein tyrosine kinases provides a fitting framework for an initial analysis of the human genome sequence.

Searching the genome

To create a catalog of protein tyrosine kinase coding regions in the human genome, we performed iterative BLAST searches against the six-frame translations of the human genomic sequences available in the public databases (Altschul et al., 1990; Walchli et al., 2000). As probes, we used the amino acid sequences from the canonical tyrosine kinase domain of known and predicted tyrosine kinase genes of vertebrates, C. elegans, and D. melanogaster. A single accession was selected for each unique sequence and the translation was examined for protein kinase motifs and reciprocal BLAST searches were done to verify the sequence had highest similarity to protein tyrosine kinases and not other protein kinase families. The results are shown in Table 2a and b. The human genome, as currently sequenced, contains 90 tyrosine kinase genes and five presumed tyrosine kinase pseudogenes. Of the 90 tyrosine kinase genes, 58 are of the receptor type as defined by encoding a protein with a predicted transmembrane domain. These 58 receptor tyrosine kinases can be grouped into 20 subfamilies based on kinase domain sequence. The 32 non-receptor tyrosine kinases fall into 10 subfamilies based on kinase domain sequence. The remaining five sequences are classified as pseudogenes by the lack of introns in the sequence, the truncation of the coding regions compared to other members of the family, the presence of in-frame termination codons, and the absence of evidence for expression. Genomic sequences for all but five of the known tyrosine kinase genes can be found in the current GenBank databases, consistent with the predicted coverage of the human genome with the present BAC (Bacterial Artificial Chromosome) tiling and sequencing status. This allows the possibility that a very small number of protein tyrosine kinase coding elements remain undetected at present.

The information in Table 2a and b is presented in a way to facilitate access to the tools and databases at the NCBI Web site (http://www.ncbi.nlm.nih.gov). Gene symbols in the first column are those most frequently used recently in the PubMed literature database. Synonyms used in the literature for human and vertebrate orthologs are listed in the second column. Symbols used in non-human species are followed by a species designation of (m) Mus musculus, (r) Rattus norvegicus, and (ch) Gallus gallus. Gene symbols in bold are those approved by HUGO Gene Nomenclature Committee (White et al., 1997). These approved symbols are used in the LocusLink curated database of linked information on defined genes (Maglott et al., 2000; Pruitt et al., 2000). Where possible, reference sequences (RefSeq) accession numbers are given for nucleotide and protein sequences. Unigene cluster numbers are given for access to Unigene EST database and related expression links (Boguski and Schuler, 1995). Genomic accession numbers can be used in conjunction with Mapviewer for graphical access to the human genome data.

Newly identified human tyrosine kinases

Five novel human kinase sequences were identified in the genome-wide search. The first is the human ortholog of the EphA6 gene of rodents. Interestingly, the human transcript as defined by several ESTs contains a truncated reading frame produced by a cryptic splice in kinase subdomain VIII. The genomic locus confirms the validity of the EST transcripts and contains putative unused exons for subdomains IX-XI. Whether the altered human EPHA6 gene product retains tyrosine kinase activity is an open question. A second potential new member of the Eph family is found on chromosome 1 and is designated as EPHX. The EPHX sequences in the genome retain the basic intron/exon structure of the Eph family kinase domains, and the predicted protein sequence is similar to the other members of the Eph family, although divergent at several conserved elements. No evidence for the transcription of this locus exists in the databases and EPHX may be a vestigial gene sequence. Another novel sequence uncovered, AATYK3, is a third member of a class of tyrosine kinases defined by the AATYK and KIAA1079 genes. AATYK3 is highly similar to the other members of the family in both kinase and non-kinase domains. The fourth novel sequence is the human ortholog of the murine Srms non-receptor tyrosine kinase and the predicted reading frame encodes a protein with high similarity to Srms in both kinase and non-kinase domains. Finally, a novel sequence with tyrosine kinase homology is found on chromosome 12 and a partial cDNA sequence exists, DKFZp761P1010. The predicted reading frame encodes a protein with weak similarity to the kinase domains of fibroblast growth factor receptors, a transmembrane domain, but lacking a signal peptide. No other potential members of this class of tyrosine kinases were detected in the human genome.

There are several tyrosine kinases found in other species for which human orthologs could not be found. The large Kin 15/Kin 16 class of receptor tyrosine kinase genes in the C. elegans genome has no identifiable orthologs in the human genome. In chickens, the src family member Yrk and the eph family member EphB5 (Cek9) lack identified mammalian orthologs. One possibility is that the EPHX sequences in the human genome are from the ancestral EphB5 gene. Finally, no sequences for the proposed human ZRK zona pelucida kinase can be detected in the human genome and the ZRK clone is most likely derived from the human MER gene (Tsai and Silver, 1996).

Distribution of human tyrosine kinase genes

The cytogenetic distribution of tyrosine kinase genes in the human genome is depicted in Figure 1. Tyrosine kinase genes can be found on 19 of the 24 human chromosomes. At least three locations show evidence of more recent gene duplication events. On chromosome 5, the highly similar PDGFRB and CSF1R genes are adjacent and contained within a single BAC clone. On chromosome 20, the FRK family members BRK and SRMS are contained within a single BAC. On chromosome 4, the TEC and TXK genes can also be found within a single BAC clone.

Classification of human tyrosine kinases

A phylogenetic analysis of the amino acid sequences of the kinase domains from the identified human tyrosine kinases is shown in Figure 2. The human tyrosine kinases may be grouped into 20 receptor and 10 non-receptor classes as marked on the right of the figure. Grouping tyrosine kinase genes by intron/exon structure closely parallels the results obtained from phylogenetic sequence analysis. For example, phylogenetic analysis of amino acid sequence places the two CSK family members apart from the three FRK family members and the eight SRC family members, even though all three families share the same overall protein domain structure (Figure 3a) (Lee et al., 1998). This distinction of the families is verified by a different intron/exon organization for each family. Within a tyrosine kinase family, the members of a single family exhibit a common intron/exon pattern, distinct from other families.

The clustering of tyrosine kinase genes into families based on kinase domain sequence also parallels the overall domain structure of the proteins. A diagram of the overall protein domain structure of a representative member of each tyrosine kinase family is shown in Figure 3a,b. The human tyrosine kinase families exhibit a wide spectrum of protein domains consistent with the numerous and varied interactions and functions of these molecules as reviewed by the publications in Table 1. The domain representations are not complete. Many families encode proteins for which some domains are not defined, given the current state of knowledge.

Mouse orthologs of human tyrosine kinase genes

The assignment of vertebrate orthologs to the human tyrosine kinase genes was done by reciprocal BLAST searches between the human, mouse, rat, and chicken sets of tyrosine kinase genes. Pairs with reciprocal best scores were assigned as orthologs and the results are shown in Table 3a and b (Walchi et al., 2000). The mouse gene symbols used are in accordance with the MGD Nomenclature Committee and LocusLink (Blake et al., 2000). The per cent identity and similarity for the protein kinase domains of the mouse and human orthologs are shown in the fourth column. Cluster numbers for the murine Unigene EST database are given. Accession numbers for identified rat and chicken orthologs complete the tables. A nearly complete correspondence between the tyrosine kinase families of man and mouse exists. There are only three human PTKs for which an orthologous murine sequence has not been discovered, and this gap is likely to be filled quickly. Conversely, there are no identified rodent tyrosine kinases for which a human ortholog does not exist. For the non-mammalian vertebrates, such as chicken, a limited number of tyrosine kinases may not have human orthologs, as discussed previously. This correspondence between the tyrosine kinase gene families of humans and mice reinforces the validity of mouse models for human diseases, especially cancer.

The application of the human genomic sequence information should greatly aid the study of protein tyrosine kinases. As a first step, the catalog of tyrosine kinase genes in the human genome should provide a foundation for further discovery of kinase involvement in disease progression and functional characterizations. The fact that the range of human protein tyrosine kinases was nearly identified prior to the genomic sequence information is a testament to the interest shown and quality of work performed by the numerous researchers devoted to protein kinases. Other less well-studied gene families are likely to have more surprises in the human genome. Continuing studies on expression patterns, functional characterizations, and disease associations of tyrosine kinases, as well as studies of genetic variations at tyrosine kinase loci, should provide a basis for the development of new therapeutics for the treatment of human disease.

Acknowledgements

We would like to thank Dr H-J Kung for valuable discussions and support. We acknowledge all those whose relevant contributions we were unable to cite in this review due to space limitations. This work was supported by NIH grant ROI CA82073.

Abram CL and Courtneidge SA. (2000). Exp. Cell Res. 254, 1-13. Article MEDLINE

Altschul SF, Gish W, Miller W, Myers EW and Lipman DJ. (1990). J. Mol. Biol. 215, 403-410. Article MEDLINE

Aringer M, Cheng A, Nelson JW, Chen M, Sudarshan C, Zhou YJ and O'Shea JJ. (1999). Life Sci. 64, 2173-2186. MEDLINE

Avraham H, Park SY, Schinkmann K and Avraham S. (2000). Cell Signal 12, 123-133. Article MEDLINE

Barbacid M. (1994). J. Neurobiol. 25, 1386-1403. MEDLINE

Barbacid M. (1995). Ann. NY Acad. Sci. 766, 442-458. MEDLINE

Baserga R. (1999). Exp. Cell Res. 253, 1-6. MEDLINE

Bateman A, Birney E, Durbin R, Eddy SR, Howe KL and Sonnhammer EL. (2000). Nucleic Acids Res. 28, 263-266. Article MEDLINE

Birchmeier C and Gherardi E. (1998). Trends Cell Biol. 8, 404-410. Article MEDLINE

Birchmeier C, Sonnenberg E, Weidner KM and Walter B. (1993). Bioessays 15, 185-190. MEDLINE

Blake JA, Eppig JT, Richardson JE and Davisson MT. (2000). Nucleic Acids Res. 28, 108-111. Article MEDLINE

Boguski MS and Schuler GD. (1995). Nat. Genet. 10, 369-371. MEDLINE

Bourette RP and Rohrschneider LR. (2000). Growth Factors 17, 155-166. MEDLINE

Bruckner K and Klein R. (1998). Curr. Opin. Neurobiol. 8, 375-382. MEDLINE

Chow LM and Veillette A. (1995). Semin. Immunol. 7, 207-226. Article MEDLINE

Chu DH, Morita CT and Weiss A. (1998). Immunol. Rev. 165, 167-180. MEDLINE

Cole PA, Sondhi D and Kim K. (1999). Pharmacol. Ther. 82, 219-229. MEDLINE

Comoglio PM and Boccaccio C. (1996). Genes Cells 1, 347-354. MEDLINE

Crosier KE and Crosier PS. (1997). Pathology 29, 131-135. MEDLINE

Danial NN and Rothman P. (2000). Oncogene 19, 2523-2531. MEDLINE

Danilkovitch A and Leonard EJ. (1999). J. Leukoc. Biol. 65, 345-348. MEDLINE

Eng C. (1999). J. Clin. Oncol. 17, 380-393. MEDLINE

Eng C and Mulligan LM. (1997). Hum. Mutat. 9, 97-109. MEDLINE

Fischer EH. (1999). Adv. Enzyme Regul. 39, 359-369. MEDLINE

Flanagan JG and Vanderhaeghen P. (1998). Annu. Rev. Neurosci. 21, 309-345. MEDLINE

Forrester WC, Dell M, Perens E and Garriga G. (1999). Nature 400, 881-885. Article MEDLINE

Frisen J, Holberg J and Barbacid M. (1999). EMBO J. 18, 5159-5165. Article MEDLINE

Gaozza E, Baker SJ, Vora RK and Reddy EP. (1997). Oncogene 15, 3127-3135. MEDLINE

Gerwins P, Skoldenberg E and Claesson-Welsh L. (2000). Crit. Rev. Oncol. Hematol. 34, 185-194. MEDLINE

Girault JA, Costa A, Derkinderen P, Studler JM and Toutant M. (1999). Trends Neurosci. 22, 257-263. Article MEDLINE

Glass DJ and Yancopoulos GD. (1997). Curr. Opin. Neurobiol. 7, 379-384. MEDLINE

Hackel PO, Zwick E, Prenzel N and Ullrich A. (1999). Curr. Opin. Cell Biol. 11, 184-189. Article MEDLINE

Hallbook F. (1999). Curr. Opin. Neurobiol. 9, 616-621. MEDLINE

Hanks SK and Hunter T. (1995). FASEB J. 9, 576-596. MEDLINE

Hanks SK and Quinn AM. (1991). Methods Enzymol. 200, 38-62. MEDLINE

Holder N and Klein R. (1999). Development 126, 2033-2044. MEDLINE

Hubbard SR, Mohammadi M and Schlessinger J. (1998). J. Biol. Chem. 273, 11987-11990. Article MEDLINE

Hubbard SR and Till JH. (2000). Annu. Rev. Biochem. 69, 373-398. MEDLINE

Hunter T. (1997). Cell 88, 333-346. MEDLINE

Hunter T. (2000). Cell 100, 113-127. MEDLINE

Hunter T and Plowman GD. (1997). Trends Biochem. Sci. 22, 18-22. Article MEDLINE

Imada K and Leonard WJ. (2000). Mol. Immunol. 37, 1-11. MEDLINE

Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B and Yamamoto T. (1997). Oncogene 14, 439-449. MEDLINE

Johnson LN, Noble ME and Owen DJ. (1996). Cell 85, 149-158. MEDLINE

Kaplan DR and Miller FD. (1997). Curr. Opin. Cell Biol. 9, 213-221. MEDLINE

Kim H and Muller WJ. (1999). Exp. Cell Res. 253, 78-87. Article MEDLINE

Klages S, Adam D, Class K, Fargnoli J, Bolen JB and Penhallow RC. (1994). Proc. Natl. Acad. Sci. USA 91, 2597-2601. MEDLINE

Klambt C. (2000). Curr. Biol. 10, R388-R391. MEDLINE

Klint P and Claesson-Welsh L. (1999). Front. Biosci. 4, D165-D177. MEDLINE

Kohmura N, Yagi T, Tomooka Y, Oyanagi M, Kominami R, Takeda N, Chiba J, Ikawa Y and Aizawa S. (1994). Mol. Cell. Biol. 14, 6915-6925. MEDLINE

Ladanyi M. (1997). Cancer Surv. 30, 59-75. MEDLINE

Ladanyi M. (2000). Am. J. Pathol. 157, 341-345. MEDLINE

Laneuville P. (1995). Semin. Immunol. 7, 255-266. Article MEDLINE

Lanier LM and Gertler FB. (2000). Curr. Opin. Neurobiol. 10, 80-87. Article MEDLINE

Lee H, Kim M, Lee KH, Kang KN and Lee ST. (1998). Mol. Cells 8, 401-407. MEDLINE

Lee J, Wang Z, Luoh SM, Wood WI and Scadden DT. (1994). Gene 138, 247-251. MEDLINE

Leonard WJ and O'Shea JJ. (1998). Annu. Rev. Immunol. 16, 293-322. MEDLINE

LeRoith D. (2000). Endocrinology 141, 1287-1288. MEDLINE

Lucini C, Castaldo L, Lamanna C, Maruccio L, Vega JA and Gargiulo G. (1999). Neurosci. Lett. 261, 163-166. MEDLINE

Maglott DR, Katz KS, Sicotte H and Pruitt KD. (2000). Nucleic Acids Res. 28, 126-128. Article MEDLINE

Mano H. (1999). Cytokine Growth Factor Rev. 10, 267-280. MEDLINE

Marino-Buslje C, Martin-Martinez M, Mizuguchi K, Siddle K and Blundell TL. (1999). Biochem. Soc. Trans. 27, 715-726. MEDLINE

Mason I. (2000). Pharm. Acta. Helv. 74, 261-264. MEDLINE

Mellitzer G, Xu Q and Wilkinson DG. (2000). Curr. Opin. Neurobiol. 10, 400-408. Article MEDLINE

Miller MA, Malik IA, Shenk MA and Steele RE. (2000). Oncogene 19, 3925-3930. MEDLINE

Morrison DK, Murakami MS and Cleghon V. (2000). J. Cell Biol. 150, F57-F62. MEDLINE

Mott HR, Owen D, Nietlispach D, Lowe PN, Manser E, Lim L and Laue ED. (1999). Nature 399, 384-388. Article MEDLINE

Muller WE, Kruse M, Blumbach B, Skorokhod A and Muller IM. (1999). Gene 238, 179-193. MEDLINE

Neet K and Hunter T. (1996). Genes Cells 1, 147-169. MEDLINE

Neubauer A, Burchert A, Maiwald C, Gruss HJ, Serke S, Huhn D, Wittig B and Liu E. (1997). Leuk. Lymphoma 25, 91-96. MEDLINE

Neufeld G, Cohen T, Gengrinovitch S and Poltorak Z. (1999). FASEB J. 13, 9-22. MEDLINE

Park SK, Lee HS and Lee ST. (1996). J. Biochem. (Tokyo) 119, 235-239. MEDLINE

Partanen J and Dumont DJ. (1999). Curr. Top. Microbiol. Immunol. 237, 159-172. MEDLINE

Pendergast AM. (1996). Curr. Opin. Cell Biol. 8, 174-181. MEDLINE

Plowman GD, Sudarsanam S, Bingham J, Whyte D and Hunter T. (1999). Proc. Natl. Acad. Sci. USA 96, 13603-13610. Article MEDLINE

Popovici C, Roubin R, Coulier F, Pontarotti P and Birnbaum D. (1999). Genome Res. 9, 1026-1039. MEDLINE

Porter AC and Vaillancourt RR. (1998). Oncogene 17, 1343-1352. MEDLINE

Pruitt KD, Katz KS, Sicotte H and Maglott DR. (2000). Trends Genet. 16, 44-47. Article MEDLINE

Rawlings DJ and Witte ON. (1995). Semin. Immunol. 7, 237-246. Article MEDLINE

Rikke BA, Murakami S and Johnson TE. (2000). Mol. Biol. Evol. 17, 671-683. MEDLINE

Robertson SC, Tynan J and Donoghue DJ. (2000). Trends Genet. 16, 368. MEDLINE

Saitou N and Nei M. (1987). Mol. Biol. Evol. 4, 406-425. MEDLINE

Sakuma M, Onodera H, Suyemitsu T and Yamasu K. (1997). Zoolog. Sci. 14, 941-946. MEDLINE

Schaeffer EM and Schwartzberg PL. (2000). Curr. Opin. Immunol. 12, 282-288. Article MEDLINE

Schenk PW and Snaar-Jagalska BE. (1999). Biochim. Biophys. Acta 1449, 1-24. MEDLINE

Schlaepfer DD and Hunter T. (1998). Trends Cell Biol. 8, 151-157. Article MEDLINE

Schlessinger J. (1997). Cell 91, 869-872. MEDLINE

Schlessinger J. (2000). Cell 100, 293-296. MEDLINE

Schlessinger J and Ullrich A. (1992). Neuron 9, 383-391. MEDLINE

Schwartzberg PL. (1998). Oncogene 17, 1463-1468. MEDLINE

Serfas MS and Tyner AL. (1998). Oncogene 17, 3435-3444. MEDLINE

Shurin MR, Esche C and Lotze MT. (1998). Cytokine Growth Factor Rev. 9, 37-48. MEDLINE

Smithgall TE, Rogers JA, Peters KL, Li J, Briggs SD, Lionberger JM, Cheng H, Shibata A, Scholtz B, Schreiner S and Dunham N. (1998). Crit. Rev. Oncog. 9, 43-62. MEDLINE

Sondhi D and Cole PA. (1999). Biochemistry 38, 11147-11155. MEDLINE

Suga H, Koyanagi M, Hoshiyama D, Ono K, Iwabe N, Kuma K and Miyata T. (1999). J. Mol. Evol. 48, 646-653. MEDLINE

Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K, Tamura S, Ueda T, Hatta T, Otani H, Terashima T, Takada S, Yamamura H, Akira S and Minami Y. (2000). Genes Cells 5, 71-78. MEDLINE

Tallquist MD, Soriano P and Klinghoffer RA. (1999). Oncogene 18, 7917-7932. MEDLINE

Tamura K and Nei M. (1993). Mol. Biol. Evol. 10, 512-526. MEDLINE

Thomas SM and Brugge JS. (1997). Annu. Rev. Cell. Dev. Biol. 13, 513-609. MEDLINE

Tsai JY and Silver LM. (1996). Science 271, 1432-1434; (discussion) 1434-1435. MEDLINE

Turner M, Schweighoffer E, Colucci F, Di Santo JP and Tybulewicz VL. (2000). Immunol. Today 21, 148-154. MEDLINE

van der Voort R, Taher TE, Derksen PW, Spaargaren M, van der Neut R and Pals ST. (2000). Adv. Cancer Res. 79, 39-90. MEDLINE

Vasioukhin V and Tyner AL. (1997). Proc. Natl. Acad. Sci. USA 94, 14477-14482. MEDLINE

Veikkola T, Karkkainen M, Claesson-Welsh L and Alitalo K. (2000). Cancer Res. 60, 203-212. MEDLINE

Vogel W. (1999). FASEB J. 13, S77-S82. MEDLINE

Walchli S, Colinge J and Hooft van Huijsduijnen R. (2000). Gene 253, 137-143. MEDLINE

Weiner HL and Zagzag D. (2000). Cancer Invest. 18, 544-554. MEDLINE

Weisberg E, Sattler M, Ewaniuk DS and Salgia R. (1997). Crit. Rev. Oncog. 8, 343-358. MEDLINE

Wells A. (1999). Int. J. Biochem. Cell Biol. 31, 637-643. Article MEDLINE

White JA, McAlpine PJ, Antonarakis S, Cann H, Eppig JT, Frazer K, Frezal J, Lancet D, Nahmias J, Pearson P, Peters J, Scott A, Scott H, Spurr N, Talbot Jr C and Povey S. (1997). Genomics 45, 468-471. Article MEDLINE

Whitehead JP, Clark SF, Urso B and James DE. (2000). Curr. Opin. Cell Biol. 12, 222-228. MEDLINE

Xu Q and Wilkinson DG. (1997). J. Mol. Med. 75, 576-586. MEDLINE

Yang WC, Collette Y, Nunes JA and Olive D. (2000). Immunity 12, 373-382. MEDLINE

Yeung CH, Sonnenberg-Riethmacher E and Cooper TG. (1998). J. Reprod. Fertil. (Suppl.). 53, 137-147.

Figure 1 Distribution of protein tyrosine kinase genes in the human genome (G-banded chromosome ideograms, courtesy of David Adler, Department of Pathology, University of Washington, USA)

Figure 2 Phylogram of the human protein tyrosine kinase family inferred from amino acid sequences of the kinase domains. The tree is constructed by the N-J method (Saitou and Nei, 1987) and the evolutionary distance is calculated by Tamura-Nei algorithm (Tamura and Nei, 1993). Numbers on each node indicate the evolutionary distance. The tree is drawn to scale and is midpoint-rooted

Figure 3 Domain structures of the human non-receptor tyrosine kinases (a) and receptor tyrosine kinases (b). Data were obtained by searching the amino acid sequences of the human tyrosine kinases against the latest version (5.5) of the Pfam database (Bateman et al., 2000). Domains sharing significant homologies to the Pfam-A alignments are used in this study. The schematics are shown to scale

Table 1 Overview of human tyrosine kinase literatures

Table 2 Summary and classification of human non-receptor tyrosine kinases

Table 3 Assignment of human non-receptor tyrosine kinases and vertebrate orthologs