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Growth and the Tyrosine Kinome
Volume 19, Issue 4, 2003
© 2003 Prime Health Consultants, Inc.
Tyrosine kinases (TKs) add phosphate moieties to tyrosine residues on proteins that typically serve as docking sites to recruit other molecules that bind and propagate signals. As such, they function as central regulators of signaling pathways that control transcription, cell cycle progression, differentiation, apoptosis and other processes that are highly relevant to growth of cells and tissues. Given this central position in regulation of growth, Bardelli et al raised the question: why have mutations in TK genes been found in only a small number of instances including certain human cancers? They speculated that mutations do exist, but have yet to be detected because the vast number of TK genes is only now becoming apparent as the human genome project unfolds. To test this idea, they took advantage of high-throughput sequencing and bioinformatics from the human genome project to search for TK mutations in a select group of cancers, colorectal cancers.

A recent analysis organized the protein kinase complement of the human genome (the "kinome") into a dendrogram containing nine broad groups or branches of genes. Bardelli et al selected one major branch, which contained three groups including 90 TK genes, 43 TK-like genes and 5 receptor guanylate cyclase genes. Mutation analysis of 813 exons from the genomic database carried out on DNA from 35 colorectal cancer cell lines yielded 14 mutations. Further analysis of DNA from 147 tumors identified 46 novel mutations in 14 genes. All of the mutations were somatic in nature based on comparison of DNA from tumor to matched normal tissues.

The authors suggested that mutations found in seven genes, which were detected in more than one tumor, were functional rather than coincidental. Based on the specific locations of the mutations, they further suggested that many of the mutations were activating in nature, i.e., they resided in key regions of the TK, such as the autoinhibitory activation loop. The authors concluded that at least 30% of colorectal cancers contain at least one mutation in the tyrosine kinome. They emphasized that an important reason to study TK genes is that they provide attractive targets for therapeutic intervention for growth disorders, noting the convincing success of targeting BCR-ABL tyrosine kinase in leukemia (Druker BJ. Cancer Cell 2002;1:31).

Bardelli A et al. Mutation Analysis of the Tyrosine Kinome in Colorectal Cancers. Science 2003;300:949.

Editor’s Comment: While this paper specifically addresses cancer, it does not take too much imagination to see its potential relevance to growth of other tissues, such as the skeleton. Indeed, achondroplasia is due to activating mutations of the FGFR3 tyrosine kinase. Given the scope of regulation necessary to orchestrate and coordinate events in a growing bone, it seems highly probable that there are other members, perhaps many, of the tyrosine kinome involved. Accordingly, mutations of these as of yet undefined TKs may underlie disorders of skeletal growth. Considering the remarkable success of Gleevec in treating chronic myelogenous leukemia by inhibiting the BCR-ABL TK, it is not inconceivable to dream of using pharmacologic manipulation of growth-plate TKs to therapeutically manage certain bone growth disturbances in the future.

William A. Horton, MD