Mike Harrison

Profile

I joined the University of Leeds at the end of 1991 after completing post-doctoral work in the lab of Prof. Tasso Melis at UC-Berkeley, where I worked on control of antenna size in photosynthetic systems. Further post-doc work with Prof. John Findlay at Leeds then led to a Wellcome Trust Career Development Fellowship (1994-1998), and appointment as a lecturer in the School of Biochemistry and Molecular Biology in 1999. I am now in the School of Biomedical Sciences, although my research interests and teaching activities remain centred around biochemistry and molecular cell biology, in particular bioenergetics, metabolism and cell signalling, with specific focus on the structure and function of the membrane protein complexes involved in these processes.

Responsibilities

• Programme Leader for Medical Sciences

Research interests

Structure, function and molecular mechanisms of membrane protein complexes

The vacuolar H+-ATPase (V-ATPase) is a membrane protein complex that works as an ATP-fuelled acid pump. It plays a central role in cell physiology, with defects in it causing bone and kidney diseases, and compounds that affect it having potential as anti-cancer drugs. The V-ATPase is a molecular-scale machine: Two rotary motors (one consuming ATP 'fuel', the other pumping acid) are linked by a rotating axle that drives the acid pump in the cell membrane. The nature of this mechanical coupling and how it actually pumps the acid remain unanswered but fundamental questions. Tackling them is a key aim of the research in my lab, but this needs higher resolution structural models of the complex. To do this we work with structural biologists and use high-resolution electron microscopy to look at the 3-D organisation of the protein (see Muench et al (2011) Q. Rev. Biophys. 44, 311; Rawson et al (2015) Structure 23, 461).

 

The V-ATPase also connects to, and is controlled by, other cellular energy pathways. How it makes the connection, and how this controls the V-ATPase, are uncertain but appear to involve protein phosphorylation signals. We are also looking at the connection between cell signalling and ATPase activity, working out in particular the changes at the molecular level that cause the ATPase to become switched off (see Muench et al (2014) J. Mol. Biol. 426, 286).

In cultured cancer cells, some forms of the V-ATPase are present in large numbers at the cell surface where they appear to play a role in helping the cell maintain a stable internal pH. We are examining how this plasma membrane localisation comes about, and the cause-and-effect relationship it might have with tumour invasiveness (see Smith et al (2016) J. Biol. Chem. 291, 8500).

Receptor tyrosine kinases are a class of membrane proteins that play crucial roles in transmitting signals from growth factors and hormones into the cell, bringing about major changes in features such cell physiology, motility, growth and regeneration. Whilst we know a great deal about the detailed structures of parts of these complex molecules from x-ray crystallography, we currently don't have detailed structures for the whole receptor. Bringing together specialists in RTK cell biology and biochemistry with experts in cryo-electron microscopy, our objective is to solve the complete structures of important RTKs in both the silent and fully active states. The aim is to achieve a better understanding of the steps at the molecular level that link growth factor/hormone binding at the cell surface to the initiation of signalling within that cell.

Currently active project areas in the lab are:

1. Structure, function and regulation of the V-ATPase
2. Control of V-ATPase function by protein kinase signalling.
3. Role of the V-ATPase in cancer: isoform function, location and navigation around the cell
4. The role of ubiquitination in Vascular Endothelial Growth Factor Receptor -1/2 function (with Dr Vas Ponnambalam).
5. Structure of Receptor Tyrosine Kinases by high-resolution cryo-electron microscopy (with Dr Stephen Muench & Dr Vas Ponnambalam).

Qualifications

• PhD, Leeds, 1990
• BSc Biochemistry/Zoology, Leeds, 1985

Student education

My teaching within the programmes offered by the School of Biomedical Sciences is largely focused on basic chemistry and biochemistry:

• Basic laboratory skills for biomedical scientists
• Core numeracy, statistical and IT skills
• Metabolism and bioenergetics
• Receptor biochemistry

I also have wide experience in providing teaching on membrane protein structure and function to biochemistry and microbiology students at all levels, and have spent significant time teaching basic biochemistry to medical students. For over 10 years, I managed a core 'biomedical sciences' module as part of the MBChB clinical medicine programme at Leeds. I also provide teaching to both BSc and MSc students on protein expression technologies, and have contributed to text books on this subject (Harrison, M.A. & McPherson, M.J. (2013) Recombinant protein expression. In: Tools and Techniques in Biomolecular Science (Divan, A. & Royds, J., eds.). Oxford University Press, Oxford). I currently manage modules across all undergraduate levels, ranging from laboratory skills to tutorial-based modules and advanced, research-themed lecture modules. As a result, I have extensive knowledge and experience of different assessment methodologies.

Studentship information

Postgraduate studentship areas:

• High resolution cryo-electron microscopy of receptor tyrosine kinases (with Dr Stephen Muench and Dr Vas Ponnambalam)
• All hands to the pump: what controls V-ATPase isoform activity at the plasma membrane of invasive cancer cells?
• Regulation of the human v-ATPase pump by protein kinase activity

See also:

• Faculty Graduate School
• FindaPhD Project details:
  • Project 24362

Modules managed

BMSC1103 - Basic Laboratory and Scientific Skills
BMSC2233 - Topics in Medical Sciences
BMSC3146 - Advanced Topics in Medical Sciences I
BMSC3236 - Advanced Topics in Medical Sciences II

Modules taught

BIOL2111/BIOC2301 - Integrated Biochemistry/Genetic Engineering
BIOL5372M - Advanced Biomolecular Technologies
BMSC1103 - Basic Laboratory and Scientific Skills
BMSC1110/SPSC1220 - Foundation modules
BMSC1213 - Basic Laboratory and Scientific Skills 2
BMSC2233 - Topics in Medical Sciences
BMSC3301 - Research Project in Biomedical Sciences
BMSC5382M - Extended Research Project
MEDI1216 - Introduction to Medical Sciences

Academic roles

UG Programme Leader - UG Medical Sciences programmes

Committees

Member of Undergraduate School Taught Student Education Committee (Programme Manager: Medical Sciences)

Research groups and institutes

• Integrative Membrane Biology