All Eukaryotic Kinases Share One Common Set of Substrates

Dysregulation of protein phosphorylation plays a major role in many diseases such as cancer and neurodegenerative disorders. In addition, the elucidation of many kinase cascades has proved pivotal for understanding and manipulating cellular behaviour in a variety of divergent eukaryotes.

Within these organisms a wide rage of kinases has been defined. The human genome contains over 500 protein kinase genes, whereas the genome of a small plant like Arabidopsis thaliana, the mouse-ear cress, contains nearly 1,000. Despite this diversity, a team led by Maikel Peppelenbosch, PhD, a professor of Cell Biology at the University Medical Center in Groningen, the Netherlands, has established that all eukaryotic kinases share a common set of substrates, nine amino acid segments shared by all proteins that are known to be phosphorylated.

The team’s work is to be published in the online, open-access journal PLoS ONE on August 22nd.

Using a peptide array, the investigators tested all kinase substrates described in the PhosphoBase phosphorylation database. They incubated them with radio actively labelled ATP as a source of phosphate, and lysates (cell content) of two species of yeast (Candida albicans and Pichia pastoris), a fungus (Fusarium solani), a plant (Triticum aeastivum, wheat), a fruit fly (Drosophila melanogaster), a mouse (Mus musculus), and man (Homo sapiens) as a source of kinases. Their results show that the large diversity of kinases tested is contrasted by a very small diversity in the substrates that are sensitive to them.

These results indicate that, although probably thousands of different kinases have developed during the 2.4 billion years of eukaryotic evolution, they show no significant functional difference. Furthermore, the results suggest the presence of a set of kinase substrates in an ancestral eukaryote that has remained unchanged in eukaryotic life, so the earliest eukaryotes may have been less ‘primitive’ than generally thought.

Since drugs targeting protein kinases are promising for the therapeutic treatment of a host of different diseases, this result may prove to be useful in the testing of such drugs.

The study was funded by the Netherlands Organization for Scientific Research (NOW). Other researchers involved were Sander H. Diks, Kaushal Parikh, and Marijke van der Sijde at the University Medical Center Groningen, Groningen, Jos Joore at Pepscan Presto BV, Lelystad, and Tita Ritsema at the Department of Phytopathology, Utrecht University, Utrecht, all in the Netherlands.

Accordingly, drugs targeting protein kinases are promising avenues for the therapeutic treatment of many different diseases.