Protein Kinase Signalling in Neuronal Function

Protein phosphorylation is a rapid and reversible molecular switch used for intracellular signalling in diverse cell biological processes. The Evans lab studies the role of protein phosphorylation in a range of neuronal processes in the healthy and diseased brain, including development, learning, neurodegeneration and neuroblastoma.

The human genome encodes over 500 kinase enzymes, grouped in families that phosphorylate proteins within specific motifs. The effects of phosphorylation are diverse and include altering protein-protein interactions, enzyme activity or subcellular localisation. Identifying the specific substrates of each kinase is important because inherited and acquired mutations in kinases and their substrates are linked with a wide range of diseases, including cancer and neurological disorders.

The Evans lab employs a variety of biochemical, proteomic, cell biological and fluorescence imaging approaches to study kinases and determine the function of their specific protein phosphorylation events. Our major goal is to determine the role of Src tyrosine kinase isoforms (C-Src, N1-Src and N2-Src) in the brain. Specific neuronal splicing events yield kinases that differ by just a few amino acids and yet have profoundly different functions. The N-Srcs have a role in neuronal development and their high expression is linked with a good prognosis in the childhood developmental cancer, neuroblastoma. We are investigating which N-Src substrates are linked with neuroblastoma prognosis and whether they provide a novel route to therapy.

We are also studying the role of Src kinases in neurodegeneration. Aberrant trafficking of amyloid precursor protein (APP) is thought to contribute to the pathology of Alzheimer’s disease. We have identified a single Src phosphorylation site in a trafficking protein, Mint1, which determines the destination of APP in neurons. We aim to establish if dysregulation of this switch-like mechanism is linked to the onset of Alzheimer’s disease.