Faculty of Biological Sciences

Dr Michael Harrison

BSc, PhD Oct 1990, Leeds
Lecturer
School of Biomedical Sciences

Background: Postdoctoral work: University of California-Berkeley, 1990-91; University of Leeds, 1991-1994. Wellcome Trust Career Development Fellowship, 1994-1998.

Contact:  Garstang 6.44a, +44(0) 113 34 37766, email address for  

Research Interests

Structure, function and molecular mechanisms of membrane protein complexes

Prostate cancer cell

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.

 

Current Projects

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).

 

Faculty Research and Innovation



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:

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
BMSC3399 - Extended Research Project Preparation
BMSC5382M - Extended Research Project
MEDI1216 - Introduction to Medical Sciences

Committees

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

Group Leader Dr Michael Harrison  (Lecturer)

Structure, function and molecular mechanisms of membrane protein complexes 

Postgraduates

Joanna Mitchell (Co-supervisor) 20% FTE
Faheem Shaik (Co-supervisor) 35% FTE