Dr Mike Tomlinson

Supervisor Details

Contact Details

School of Biosciences, University of Birmingham

Scientific Background

Research Interests

Mike’s research focuses on tetraspanin membrane proteins as potential therapeutic targets for major human diseases such as cancer, cardiovascular and inflammatory diseases. He enjoys research-led teaching on the molecular mechanisms underlying these diseases.

Mike’s group investigates how tetraspanins regulate other important membrane proteins on the surface of human cells.

Mike has recently established a new paradigm in human membrane protein biology, whereby the important cell surface ‘molecular scissor’ ADAM10 is not one scissor, but six different scissors depending on which one of six tetraspanins, termed the TspanC8s, it is associated with – his ‘six scissor’ hypothesis. This has major implications for future therapeutic targeting of diseases such as cancer, Alzheimer’s disease, asthma and inflammatory diseases including those leading to heart attack and stroke. Targeting all six ADAM10 scissors in these diseases would be too toxic for the patient, but targeting the one scissor that is causing the disease has great potential.

Mike has also identified tetraspanin Tspan18 as a critical regulator of the store-operated Ca²⁺entry channel Orai1 on endothelial cells, and as a potential therapeutic target for thrombo-inflammatory diseases such as deep vein thrombosis.

Scientific Inspiration

Professor Alan Williams (1945-1992), FRS, Head of the MRC Cellular Immunology Unit and Sir William Dunn School of Pathology in Oxford. My supervisor at the start of my PhD. Inspired me to work on cell surface proteins.

Research Groups

Structural and Molecular Cell Biology

Vascular Tetraspanin Research Group

Centre of Membrane Proteins and Receptors (COMPARE)

Supervision Style

In three words or phrases: Laid-back, supportive, collaborative.

Provision of Training

Your training will be supervised by me or by my experienced post docs/PhD students, leading to more independence later.

Progression Monitoring and Management

I will expect you to take full ownership of your progression but come to me when you need help troubleshooting.

Communication

I am known to email my team/PhD students at all hours of the day and night, as I have four school-age kids so need to work flexibly. However, I will not expect you to respond outside of normal working hours.

PhD Students can expect scheduled meetings with me:

In a group meeting

At least once per week

In year 1 of PhD study

At least once per week

In year 2 of PhD study

At least once per fortnight

In year 3 of PhD study

At least once per month

The meetings will be face to face and I am usually contactable for an instant response (if required) on every working day.

Working Pattern

The timing of work in my lab is flexible and I expect students to manage their own time, although there will be occasions when they are being shown techniques or working as a team, when they will need to adapt to the working times of others.

Notice Period for Feedback

I need at least 1 week’s notice to provide feedback on written work of up to 5000 words.

MIBTP Project Details

Current Projects (2024-25)

Primary supervisor for:

Investigating the structure and function of tetraspanin membrane proteins

See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.

Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).

Investigating the structure and function of tetraspanin membrane proteins

Secondary Supervisor(s): Professor Tim Dafforn

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Structural Biology)

Project Outline

Tetraspanin membrane proteins are emerging as potential therapeutic targets for major human disorders such as cancer, infection and inflammatory diseases. Tetraspanins function by regulating other membrane proteins including certain proteases, ion channels and adhesion proteins. The tetraspanins are important for the trafficking of these partner proteins to the cell surface and for their lateral mobility and clustering on the cell surface. There are 33 tetraspanins in humans but many remain functionally uncharacterised. Nevertheless, experiments in tetraspanin knockout mice and cultured cells, and genome-wide association studies, are revealing tetraspanin links to human disease. Moreover, recent structural studies show that tetraspanins have cone-shaped structures with the potential for conformational change and drug targeting [1].

The overarching aim of this project is to discover novel mechanisms of tetraspanin action using our recently developed lipid nanodisc technology, namely styrene maleic acid lipid particles (SMALPs). SMALPs are 10 nm diameter particles containing discs of the plasma membrane and a surrounding belt of styrene maleic acid (SMA) copolymer. The SMA effectively acts as a ‘cookie cutter’ when applied to cultured cells, in generating discs of membrane proteins encapsulated within the lipid bilayer. Importantly, membrane protein complexes are retained within SMALPs, enabling their functional and structural characterisation in their native lipid environment. Our analyses of SMALPs on native protein gels using a novel methodology, SMA-polyacrylamide gel electrophoresis (PAGE) [2], has revealed new tetraspanin interacting partners.

The objectives of the project are as follows:

To identify novel tetraspanin interaction partners using SMA-PAGE and mass spectrometry proteomics.
To investigate how tetraspanins regulate the identified partners using CRISPR/Cas9 knockout of the tetraspanins and functional assays in cultured cells.
To gain structural information on tetraspanin complexes with partner proteins in SMALPs.

The impact of the project will be the identification of novel mechanisms by which tetraspanins regulate cell function, thus enabling future translational work on tetraspanins as drug targets in human disease.

References

1. Koo CZ, Matthews AL, Harrison N, Szyroka J, Nieswandt B, Gardiner EE, Poulter NS, Tomlinson MG. The Platelet Collagen Receptor GPVI Is Cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 Molecular Scissors. Int J Mol Sci 2022 23: 2440.

2. Wang X, Slater A, Lee SC, Harrison N, Pollock NL, Bakker SE, Navarro S, Nieswandt B, Dafforn TR, García Á, Watson SP, Tomlinson MG. Purification and characterisation of the platelet-activating GPVI/FcRγ complex in SMALPs. Arch Biochem Biophys 2024 754:109944.