The Homo sapiens genome, with ~31,000 genes, has a predicted total of 518 protein kinase genes (1.7% of all genes) . Of these 478 are in the canonical ePK family (Table 1), and the others are divided between 9 small aPK families, which include the PIKK (PI3 kinase-like kinase), the PDHK (pyruvate dehydrogenase kinase) and alpha kinase (E2F kinase) families. There are 90 tyrosine kinase genes (16% of all protein kinases); several of the tyrosine kinase families present in Drosophila and C. elegans have undergone significant expansion in mammals (e.g. Eph receptor tyrosine kinases, where there are 14 members in humans, and only 1 in Drosophila and 1 in C. elegans). The total number of protein kinases is about half that predicted 15 years ago , but it is still a strikingly large number, comprising about 1.7% of all human genes. Moreover, the total number of protein kinase gene products is surely much greater than 518, due to the expression of alternatively spliced forms, which are known for many well-studied protein kinases. A few new protein kinase families arose during the evolution of vertebrates, including the Tie and Axl families of receptor tyrosine kinases, which play roles in angio-genesis and immune system homeostasis respectively. New serine kinase families are also present, such as Trio, which is involved in secondary myogenesis and neural organization. Our analysis of the mouse kinome is not as complete, but >95% of the human protein kinases have orthologues in the mouse, and it seems likely that the mouse kinome will be very similar indeed to the human kinome .
Our extensive analysis of the human kinome has revealed a number of other features . Out of the 478 conventional ePK catalytic domains, 50 (~10%) are missing one or more of the 3 conserved catalytic residues (Lys72/Asp166/Asp184 in PKA C subunit) suggesting that most of them lack catalytic activity. These "kinase domains" may serve as docking platforms or scaffolds (e.g., ErbB3 and ILK), structural elements (receptor guanylyl cyclase kinase homology domains) and/or regulatory domains, which might bind and sense ATP levels. Many of these catalytically-dead protein kinases have been conserved throughout evolution (e.g., ILK and Derailed/RYK), implying that they serve a critical function in the absence of catalytic activity .
There are 106 predicted pseudogenes in the human genome that contain recognizable elements of the protein kinase catalytic domain (~20% of the total number of protein kinases), as defined by a lack of ESTs, reading frames with stop codons, and in many cases (75) a lack of introns, indicating that these genes underwent retrotransposition ("processed pseudogenes). For reasons that are unclear, some protein kinase families have a very high ratio of pseudo-genes to functional genes (e.g., MARK 28:4). Since the prediction of pseudogenes is not an exact science, some of these 106 genes may ultimately prove to have functional products, although possibly not active protein kinases.
The kinome analysis also has implications for human disease. Mutational activation/inactivation and overexpression of protein kinase genes is a frequent cause of hereditary and sporadic human disease. For instance, as many as half of the 90 tyrosine kinases have been implicated in cancer, through mutational activation or overexpression. For this reason, one might certainly expect mutation of some of the new protein kinase genes revealed by genomic analysis to be causal in human disease. Our analysis indicates that 80 protein kinase genes map to chromosomal disease loci, and these are candidate genes for the causative mutation. In addition, 164 protein kinase genes map to amplicons found in tumors.
Protein kinase catalytic domain function is often dependent on additional domains in the protein, which serve to regulate activity, localize, and recruit regulatory proteins/second messengers and substrates. The nature of these domains can provide insight into the functions of new protein kinases. About half the protein kinases are predicted to have additional domains, many of which are implicated in signaling processes. Of the tyrosine kinases, 25 have P.Tyr-binding SH2 domains that play a cardinal role in establishing tyro-sine phosphorylation based signaling networks. In contrast, perhaps surprisingly, only one serine kinase contains a P.Ser/Thr-binding domain (an FHA domain in CHK2). In addition, 46 protein kinases have domains that interact with other proteins (e.g., SH3); 42 protein kinases have lipid interaction domains (e.g., PH) (present in both tyrosine and serine kinases); 38 protein kinases have domains linked to small GTPase signaling (present in both tyrosine and serine kinases); and 28 protein kinases have domains linked to calcium signaling (all are serine kinases). Generally, most members of a protein kinase family have the same constellation of ancillary domains, but there are some exceptions. A complete listing of additional domains found in human protein kinases is given at http:// kinase.com/.
Two major new groups of protein kinase are revealed in metazoa; tyrosine kinase (TK) (Figure 2) and TK-like. Many of these latter protein kinases are engaged in intercellular signaling, an activity vital for the development and viability of multicellular organisms. Tyrosine kinases rely on P.Tyr-binding domains for recruiting signaling proteins to transmit the signal, and the evolution of tyrosine phos-phorylation based signaling may have depended on the development of SH2 domains. P.Tyr-specific tyrosine phos-phatases are also a requisite, but members of the PTP family are already present in the yeasts, where their function is to dephosphorylate Cdc28/Cdc2 and the MAP kinases. Choanoflagellates, which are protists that can exist in multi-cellular colonies, possess at least one receptor tyrosine kinase, suggesting that tyrosine kinases may have evolved prior to the emergence of true metazoans, and indeed this may have been an essential step .
There are 8 protein kinase families present in humans and nematodes but not flies (e.g., Met/HGF receptor). These could have been present in the common ancestor, but lost as the insect lineage evolved. Fifteen protein kinase families are unique to C. elegans, and these may have evolved to serve specialized functions in the nematode. As discussed earlier, there are 18 families common to Drosophila and humans not found in C. elegans, which could have been lost in the evolution of nematodes from the common ancestor, or they could have evolved later. Finally, there are 13 protein kinase families unique to the human kinome, which presumably evolved hand in hand with the vertebrate lineage. As indicated, these serve functions in differentiation of novel cell types and tissue structures, particularly the vascular, immune and nervous systems. In terms of vertebrate kinome evolution, our ongoing analysis of the pufferfish (Fugu rubripes) genome sequence, and of the zebrafish (Danio rerio) when it becomes available, will surely be revealing. The various shared and unique protein kinase families in the yeasts, worms, flies, and humans can be explored online at http:// kinase.com/.
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