We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

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We have determined the full protein kinase (PK) complement (kinome) of mouse. This set of 540 genes includes many novel kinases and corrections or extensions to >150 published sequences. The mouse has orthologs for 510 of the 518 human PKs. Nonorthologous kinases arise only by retrotransposition and gene decay. Orthologous kinase pairs vary in sequence conservation along their length, creating a map of functionally important regions for every kinase pair. Many species-specific sequence inserts exist and are frequently alternatively spliced, allowing for the creation of evolutionary lineage-specific functions. Ninetyseven kinase pseudogenes were found, all distinct from the 107 human kinase pseudogenes. Chromosomal mapping links 163 kinases to mutant phenotypes and unlocks the use of mouse genetics to determine functions of orthologous human kinases. E ukaryotic protein kinases (PKs) constitute one of the largest of mammalian gene families and are key regulators of a wide variety of conserved cellular processes including cell cycle, cell growth and death, metabolism, transcription, morphology and motility, and differentiation. By adding phosphate groups to substrate proteins, kinases alter the activity, location, and lifetime of a large fraction of proteins and coordinate complex cellular functions. Most PKs belong to a single superfamily containing a conserved eukaryotic PK (ePK) catalytic domain. The remaining, atypical PKs (aPKs), for the most part lack sequence similarity to the ePK domain but are known to have catalytic activity. Fifty-one distinct kinase subfamilies are conserved from yeast to human, reflecting the ancient diversity of kinase functions (1). The recent publication of a comprehensive catalog of 518 human kinases (2) includes scores of novel or poorly understood kinases. The draft mouse genome now provides a key to better understand each human kinase, by comparative analysis of protein and regulatory DNA sequences, and by use of mouse genetics and functional assays to probe the shared functions of mouse kinases and their human orthologs. The detailed comparison of such a large superfamily also casts light on the current state and utility of the draft mouse genome.The Ϸ70 million years that separate mouse from human have allowed evolution to test the functional effect of mutations throughout the sequence of every gene. This allows a mapping of functionally important conserved regions within most genes. Initial analysis of the mouse genome (3) showed that within protein coding regions, synonymous nucleotide substitutions (those that do not change protein sequence) occur at a rate [synonymous substitution rate (Ks)] of Ϸ0.6 substitutions per base between mouse and human orthologs, whereas nonsynonymous substitutions are selectively reduced, to a rate [nonsynonymous substitution rate (Ka)] of Ϸ0.01-0.1 per base, indicating that most protein sequence changes are rejected by evolution. Accordingly, protein sequence conservation ranges from an average of 71% for regions outside of known domains, to 9...

Caenorhabditis elegans should soon be the first multicellular organism whose complete genomic sequence has been determined. This achievement provides a unique opportunity for a comprehensive assessment of the signal transduction molecules required for the existence of a multicellular animal. Although the worm C. elegans may not much resemble humans, the molecules that regulate signal transduction in these two organisms prove to be quite similar. We focus here on the content and diversity of protein kinases present in worms, together with an assessment of other classes of proteins that regulate protein phosphorylation. By systematic analysis of the 19,099 predicted C. elegans proteins, and thorough analysis of the finished and unfinished genomic sequences, we have identified 411 full length protein kinases and 21 partial kinase fragments. We also describe 82 additional proteins that are predicted to be structurally similar to conventional protein kinases even though they share minimal primary sequence identity. Finally, the richness of phosphorylation-dependent signaling pathways in worms is further supported with the identification of 185 protein phosphatases and 128 phosphoprotein-binding domains (SH2, PTB, STYX, SBF, 14-3-3, FHA, and WW) in the worm genome. R eversible protein phosphorylation plays a central role in regulating basic functions of all eukaryotes such as DNA replication, cell cycle control, gene transcription, protein translation, and energy metabolism. Protein phosphorylation is also required for more advanced functions in higher eukaryotes such as cell, organ, and limb differentiation, cell survival, synaptic transmission, cell-substratum and cell-cell communication, and to mediate complex interactions with the external environment. Because aberrant protein phosphorylation is commonly the cause of cancer and other human diseases, a comprehensive knowledge of the key enzymes that regulate these functions can provide the basis for novel therapeutic intervention strategies.The genomic revolution promises to provide a new paradigm for drug discovery, allowing one to selectively target the molecular basis of human disease. The completion of the Caenorhabditis elegans genome sequence gives us an opportunity to decipher the molecular nature of its signal transduction machinery. Several global analyses of proteins and protein domains present in C. elegans have been presented elsewhere (1-4), revealing that protein kinases comprise the second largest family of protein domains in worms. The three most frequently occurring protein domains found in worms are seven transmembrane chemoreceptors (650 domains, 3.5% of genome), protein kinases (496 domains, 2.6% of genome), and zinc finger C4 domains, including nuclear hormone receptors (275 domains, 1.4% of genome). A more in-depth analysis has been performed on the 535 worm proteins containing zinc-binding domains, including the C4, C2H2, and C3HC4 ring finger types (3), and on the 83 worm homeobox transcription factors (4). Here, we present a comparative ana...

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