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A Concerned Scientist

Concerned About the Assaults on Science

Friday, March 31, 2006

The Dicty Kinome


PLoS Genetics - Protein kinases are eukaryotic enzymes involved in cell communication pathways, and transmit information from outside the cell or between subcellular components within the cell. About 2.5% of genes code for protein kinases, and mutations in many of these cause human disease. As this class of protein is heavily studied and highly relevant to the study of cancer and many other physiological and pathological cell behaviors, I find the elucidation of organims' "kinomes" to be of interest. Oh, and one such kinase, Focal Adhesion Kinase (FAK), is the focus of my dissertation research of course.

The link to evolution and conserved genes is evident right from the get-go:
Kinases are not a monolithic family, but rather have very distinct functions that are often conserved across evolution. Using pairwise and multiple sequence alignments, tree analysis and subfamily hidden Markov models (HMMs), we classified all Dictyostelium kinases to a hierarchical system of groups, families, and subfamilies (Table S2). Classifying the Dictyostelium kinases in this way enabled us to compare orthologous sets of kinases over large evolutionary distances, where a one-to-one orthologous relationship between proteins usually does not exist. This analysis allowed us to discern the likely evolutionary lineages of the Dictyostelium kinases and to assign possible functions to unstudied kinase genes. At the broadest level of kinase classification several conclusions can be made (Figure 2).
It's pretty neat work, and the paper does a gene-by-gene analysis of how many of the kinases are conserved throughout metazoa, while others show evolutionary distributions reflecting scenarios of gene expansion, divergence, and loss.

The conclusions take the point home (emphasis mine):
The comprehensive catalog of Dictyostelium kinases presented here provides insights into the early evolution of protein kinases, and a resource for future signaling research in this organism. Since kinases frequently act in concert, and are key modulators of most cellular pathways, experimental whole-kinome approaches may be fruitful in dissecting Dictyostelium signaling and cell biology. In other kinomes, large scale knockouts, RNAi, and protein chips have been employed successfully, and such technologies may now also be applied to Dictyostelium. These may be integrated with global protein interaction maps and expression profiles, and correlated with the emerging data from other species to understand both conserved and Dictyostelium-specific variants in kinase signaling pathways.

While conservation of function is a major theme, this study also indicates plasticity and variation. For instance, metazoan BRSK and CDK5 kinases function predominantly in neurite outgrowth and neurotransmitter release in the brain, yet these functions must have evolved from a non-neuronal one in their common ancestor with Dictyostelium. There are also cases of possible functional displacement. For example, the myosin light-chain kinase activity in Dictyostelium is carried out by a related CAMK1 kinase (MLCK-A), and signaling from lipids and small GTPases to myosin is mediated through the PH and CRIB domains of DMPK kinases in metazoans, but the PH and CRIB domains of a PAK kinase in Dictyostelium. The unique absence of PKC isozymes in Dictyostelium, coupled with the Dictyostelium-specific presence of C1 domains on other kinases is also an intriguing structural shift that may indicate displacement of function.

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