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Our lab is interested in the mechanism by which dual-specificity tyrosine-phosphorylation-regulated protein kinases (DYRKs) and glycogen synthase kinase 3s (GSK-3s) are regulated.
The phosphorylation of proteins on serine, threonine or tyrosine residues is arguably the most pervasive and important post-translational modification affecting cell life. Phosphorylation plays key roles in diverse processes such as cellular proliferation, differentiation, motility, metabolism and gene expression. Abnormal phosphorylation contributes to a very large number of human diseases, including cancer, developmental abnormality, diabetes, inflammation and neurological disorders. The DYRK family of kinases, for example, is strongly implicated in Down syndrome, microcephaly, cancer and Alzheimer's disease.
For many diseases, protein kinases represent a point for therapeutic intervention, and ~30 percent of all research spending on drug development focuses on protein kinase inhibitors. GSK-3 is implicated in a variety of human diseases, and many pharmaceutical companies are striving to develop small molecule inhibitors of this protein for the treatment of diabetes, Alzheimer’s, bipolar affective disorders and other neurological diseases. Understanding the molecular basis of kinase regulation therefore represents a fundamental challenge for basic and applied science. Our lab uses molecular biology and Drosophila genetics to better understand fundamental mechanisms of protein kinase regulation and the role these enzymes play in developmental signal transduction pathways.
One of the most important modes of protein kinase regulation is the phosphorylation of key residues in the activation loop of the kinase domain; an event that can increase kinase activity by two to five orders of magnitude. Previous work in our laboratory identified a novel mechanism whereby DYRKs and GSK-3 enzymes are activated. DYRKs and GSK-3 employ a short-lived transitional intermediate form of the kinase to autophosphorylate an essential tyrosine in the activation loop using an intramolecular mechanism. This intramolecular event occurs during the initial folding of the protein converting the kinases into specific intermolecular serine / threonine kinases. The intermediates differ in residue and substrate specificity, and sensitivity to small-molecule inhibitors, compared to their mature counterpart. The identification of protein kinase intermediates demonstrates that DYRKs, GSK-3, and other kinases activated in this way can be targeted at two levels; the transitory intermediate and the mature active enzyme.
Lochhead PA, Kinstrie R, Sibbet G, Rawjee T, Morrice N, Cleghon V. A chaperone-dependent GSK3β transitional intermediate mediates activation-loop autophosphorylation. Molecular Cell. 24:627-33. 2006.
Kinstrie R, Lochhead PA, Sibbet G, Morrice N, Cleghon V. dDYRK2 and Minibrain interact with the chromatin remodeling factors SNR1 and TRX. Biochem J. 398:45-54. 2006.
Lochhead PA, Sibbet G, Morrice N, Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell. 121:925-36. 2005.
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