Cell Signalling and Cancer Group
Breast Cancer, mitosis and cell proliferation
Our laboratory is interested in the identification and functional characterisation of protein kinases that contribute actively to malignant transformation. A particular focus is directed towards the PSK/TAO family of protein kinases, which provide components for the mitogen-activated protein kinase (MAPK) signalling pathways and play important roles in the regulation of cell growth and the cytoskeleton. PSKs bind and regulate microtubule dynamics and organisation and control microtubule-dependent processes including mitosis and cell division. Current studies are using a wide array of molecular and cell imaging techniques to investigate how PSK/TAO kinases act mechanistically to control malignant cell growth and breast cancer development. Novel small molecule inhibitors for PSKs have been developed and are being tested to validate these kinases as suitable drug targets for breast cancer therapy.
Figure 1: PSKs bind and regulate microtubules. Cells are immunostained to show microinjected PSK1 (red) and microtubules (green). The association of PSK1 with microtubules results in the production of perinuclear microtubule cables that are nocodazole-resistant and contain increased levels of acetylated α-tubulin (first image below). Cancer cells were co-stained to show phosphorylated and catalytically active PSK kinases (red), microtubules (green) and DNA (Blue) (second image below).
Alzheimer’s disease, tau and microtubules
In Alzheimer’s disease (AD), tau is highly phosphorylated and aggregated into neurofibrillary tangles, which likely contribute directly to neuronal cell death and neurodegeneration. Consequently, there is much interest in the identification of protein kinases responsible for the pathological phosphorylation of tau, as these enzymes could offer suitable targets for drug inhibition and therapy. We have identified an unusual kinase family called PSKs, which bind and regulate microtubules and phosphorylate tau on more than 40 residues in vitro, including sites that control tau affinity for microtubules and their stability. PSKs are normally activated catalytically during early embryonic neuronal differentiation but we have detected aberrant activation of PSKs where phosphorylated tau and neurofibrillary tangles occur in AD brain. Current studies are using imaging techniques to determine how PSKs act mechanistically to regulate tau phosphorylation, microtubule dynamics and morphogenesis in cultured primary cortical neurons as well as mature neurons and AD. Novel small molecule inhibitors for PSKs are being characterized and a major objective of the laboratory is to validate these kinases as suitable therapeutic targets for dementia treatment.
Figure 2: PSKs are activated at tangles in AD brain and in primary neurons.
A) AD (Braak VI) brains were immunostained with antibody to detect phosphorylated and catalytically active PSK-pS181, which co-localizes with tangles.
B) Primary rat cortical neurons were transfected with pCAGS-PSK1-IRES-EGFP (PSK1-IRES-GFP). PSK1-IRES-GFP transfected neurons are stained with the dendritic marker Map2 (red) and the axonal marker Tau1 (magenta). Nuclei are counterstained with DAPI (blue).
Our work is currently funded by Breast Cancer Now and Alzheimer’s Research UK.
- Morris JDH et al. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) are activated in mitosis and contribute to mitotic cell rounding and spindle positioning. 2011. J. Biol. Chem. 285. 30161-70.
- Morris JDH et al. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer Disease. 2013. J. Biol. Chem. 288. 15418-29.
Dr Jonathan Morris by email.