Centre for Molecular Cell Biology

Research Information

Cell Signalling encompasses regulated changes in cell behaviour in response to a stimulus, and is mediated by a diverse array of co-ordinated biochemical pathways. Individual signal transduction events can take many forms, such as translocation of proteins from one part of the cell to another, covalent modification, and formation or dissociation of molecular complexes. Aberrant changes in signalling can have drastically detrimental effects on a wide range of cell functions, and there is consequently enormous academic and industrial interest in signalling pathways.
 
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Phosphoinositides (PIs) are a group of 8 membrane lipids that differ in phosphorylation at the 3, 4 and 5 positions of their inositol head group. These subtle differences specify which proteins and signalling pathways are targeted.

Complexity arises from degeneracy in the enzyme activities that add or remove phosphate residues.

Additional complexity arises from the ability of PI kinases to act on more than one target membrane and regulate more than one target pathway.
Our aim is to understand the activity of specific PIs in health and disease.
 

In a broad series of studies we have purified, cloned and studied many human PI kinases and transfer proteins. Our current focus is on the biosynthesis and functions of phosphatidylinositol (PtdIns) 4-phosphate, which lies upstream of phospholipase C (PLC) and PI 3-kinase (PI3K) signalling pathways. In addition to this role as a signalling precursor, PtdIns 4-phosphate is now believed to have its own signalling targets.

We have (i) purified and cloned the type 2 PtdIns 4-kinases (PI4K2) that define a new structural family; (ii) identified different mechanisms by which PI4K2 activity can be regulated, and mechanisms that determine its subcellular localisation; (iii) investigated rafting of this enzyme arising from its palmitoylation; (iv) used live cell (4D) imaging to determine the role of PI4K2 in vesicle trafficking and receptor signalling.

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Finally our translational studies with Royal Free collaborators using genetrap technology have revealed that loss of PI4K2 activity causes a late-onset neurodegenerative disease similar to Hereditary Spastic Paraplegia.

PROTEOMIC studies within the Proteomics Unit of the Royal Free Centre for Biomedical Science have been conducted in selected collaborations with clinical experts on this campus and beyond to identify candidate biomarkers and therapeutic targets for human diseases. We employ mass spectrometry to compare complex protein mixtures from normal and disease tissue or cultured cells, followed by rigorous validation in patient populations.

Recently we co-founded UCL Proteomics in order to combine expertise across UCL and undertake ambitious research programmes.