Dr Michael Fry - University of Reading

Staff Profile:Dr Michael Fry

Name:

Dr Mike Fry

Job Title:

Academic/Director of Teaching & Learning, Harborne Building

Responsibilities:

Areas of Interest:

Research Interests:

Our recent research can be divided into three related signalling topics: 1) the analysis of phosphoinositide (PI) 3-kinases (and in particular the class II PI 3-kinase enzymes) in signalling processes in normal and diseased cells and tissue, 2) the use of proteomics to study protein kinase signalling and 3) the characterization of glycogen synthase kinase 3 and its role in the Wnt signalling pathway and in platelet signalling.

Phosphoinositide (PI) 3-kinases

I have worked on the PI 3-kinase family of lipid kinases since they were first identified in the mid-1980s as a novel activity associated with activated growth factor receptors and oncogene products. PI 3-kinase activity is now linked to diverse cellular processes including cell growth and proliferation, cell differentiation, cell survival, cell motility, the regulation of gene expression and intracellular protein trafficking. They are also linked to a number of disease states including inflammation, diabetes, heart disease and atherosclerosis and cancer. This makes them potentially interesting therapeutic targets. In the last few years our focus has been on identifying and characterizing the full complement of PI 3-kinase-related enzymes in normal and malignant breast tissue. We identified a total of eight distinct mammalian PI 3-kinases and went on to cDNA clone of two novel PI 3-kinase isoforms called PI3K-C2beta/HsC2-PI3K and PI3K-C2gamma respectively. These enzymes belong to the Class II PI 3-kinase subfamily and little is known about their function. We have found that they are activated by growth factor receptors and we are currently investigating their contribution to receptor stimulated signalling pathways and to the diseased state using live-cell confocal microscopy, RNA interference (RNAi) and proteomic approaches. A recent collaboration with scientists at UCL has led to us identifying the PI3K-C2beta enzyme as playing an important role in cell migration that may result in it being important in the metastasis of cancer cells. With the increased accessibility of large-scale technologies such as RNAi and proteomics we are currently looking into more global approaches to the analysis of PI 3-kinase signalling in cells.

Proteomic analysis of protein kinases

Current predictions suggest that there are 518 protein kinases in the human genome. These enzymes play critical roles in the regulation of many cellular processes and are often implicated in various diseases such as cancer and diabetes. Selective inhibitors have been widely used to discover the cellular signalling pathways in which particular kinases function, but also more recently also as potential therapeutic agents (e.g., Gleevac). Several recent proteomic studies using immobilised kinase inhibitors as affinity reagents have shown that the spectrum of kinases that so called specific or selective inhibitors bind is wider that was initially thought. They have also highlighted other kinases that may be important therapeutic targets for certain cancers and have suggested other interpretations as to which kinase may control certain cellular processes. We are currently using this immobilised inhibitor approach (in collaboration with the Reading Biocentre) to probe various aspects of cell signalling and plan in future to develop the approach to investigate wider issues such as which kinases are expressed in which cell types, and to study the activation/post translation modification state of kinases and the complexes they form with other signalling proteins.

Wnt signaling

The Wnt signalling pathway is important during many developmental processes and also in diseases, e.g., cancer. The pathway was originally defined by epigenetic studies in Drosophila and proved to be technically difficult to study at a biochemical level. We were the first group to show that a Wnt ligand could regulate glycogen synthase kinase-3 (GSK-3) activity in a mammalian cell context. Our current studies on this pathway are aimed at looking at the signalling elements involved in early steps of the signalling pathway between the Wnt receptor and intracellular signalling components such as the adaptor molecule, Dishevelled, (Dvl), and GSK-3. In particular our efforts are focused on the role of the lipid second messengers which are generated rapidly upon Wnt binding to receptor, analysing the mechanism of their generation and the downstream signalling components to which they couple.

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