Professor Ian GanleyFRSE

We are interested in a cell protective mechanism termed autophagy.

The cells of our body are constantly exposed to potentially damaging agents from both external sources, such as the sun's harmful UV rays or pathogenic bacteria, as well as internal sources, including free radicals produced by the cells metabolic pathways. Thankfully we have multiple mechanisms to help us cope with this onslaught. One such protection mechanism is autophagy (which literally means self-eating), whereby damaged and unwanted cellular components are targeted for degradation and recycling. These components are engulfed by a specialised structure known as the autophagosome and delivered to the digestive lysosome. This essential process prevents the cell from ending up a rubbish dump, and because of this, impaired autophagy has been linked to many diseases.

What are the signals that initiate autophagy?

We want to decipher the phosphorylation and ubiquitylation events that switch on autophagy and determine how these pathways target specific cellular components. A large part of our work focusses on two autophagy-essential kinase complexes containing either the protein kinase ULK1 or the lipid kinase VPS34. It is thought that both kinase complexes play an important role in non-specific autophagy (the random targeting of subcellular components) as well as specific autophagy. We are trying to determine how these complexes are turned on or off and if they perform the same function in specific vs. non-specific autophagy.

Can autophagy be targeted to treat disease?

To aid in studying how specific components are targeted, we have developed a simple and robust assay to monitor mitophagy, the specific autophagy of mitochondria. Dysfunctional mitophagy has been linked to many diseases including cancer, Parkinson’s and heart disease. With the aid of our assay, we have uncovered mitophagy-inducing pathways and are now characterising how the interplay between phosphorylation and ubiquitylation activates the autophagy machinery to drive mitochondrial degradation. It is our hope that modulation of these identified pathways will have therapeutic value.

Impact

Commercial Impact

In collaboration with the pharmaceutical industry via the Division of Signal Transduction Therapy collaboration with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck Serono and Pfizer the research outputs from my group contribute to accelerating the development of company drug development programmes through access to research data and reagents. Reagents are also commercialised to provide access to the wider scientific community via license arrangements with companies such as Millipore, AbCam and Ubiquigent.

Research Impact

• Developed a novel assay to specifically monitor autophagic degradation of mitochondria and uncovered a role for iron in this process
• Identified and characterised the autophagy-essential ULK1-ATG13-FIP200 kinase complex that plays a key role in autophagy induction
• Demonstrated that endosomes and autophagosomes fuse with lysosomes by different mechanisms
• Proved the existence of distinct intracellular transport routes between endosomes and the trans-Golgi

Selected Publications

Allen GFG, Toth R, James J, Ganley IG. (2013)
Loss of iron triggers PINK1/Parkin-independent mitophagy.
EMBO Rep.

Ganley, I. G., Wong, P. M., Gammoh, N. and Jiang, X. (2011).
Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest.
Mol Cell 42, pp. 731-743

Ganley, I. G., Lam du, H., Wang, J., Ding, X., Chen, S. and Jiang, X. (2009).
ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy.
J Biol Chem 284, 12297-12305

Ganley, I. G., Espinosa, E. and Pfeffer, S. R. (2008).
A syntaxin 10-SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells.
J Cell Biol 180, 159-172

Ganley, I. G. and Pfeffer, S. R. (2006).
Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells.
J Biol Chem 281, 17890-17899

Ganley, I. G., Carroll, K., Bittova, L. and Pfeffer, S. (2004).
Rab9 GTPase regulates late endosome size and requires effector interaction for its stability.
Mol Biol Cell 15, 5420-5430

Ganley, I. G., Walker, S. J., Manifava, M., Li, D., Brown, H. A. and Ktistakis, N. T. (2001).
Interaction of phospholipase D1 with a casein-kinase-2-like serine kinase.
Biochem J 354, 369-378

Nottingham, R. M., Ganley, I. G., Barr, F. A., Lambright, D. G. and Pfeffer, S. R. (2011).
RUTBC1 Protein, a Rab9A Effector That Activates GTP Hydrolysis by Rab32 and Rab33B Proteins.
J Biol Chem 286, 33213-33222

Groves, M. J., Johnson, C. E., James, J., Prescott, A. R., Cunningham, J., Haydock, S., Pepper, C., Fegan, C., Pirrie, L., Westwood, N. J., Coates, P. J., Ganley, I. G. and Tauro, S. (2013).
p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia.
Br J Cancer Epub Oct 3

Hau, A. M., Greenwood, J. A., Lohr, C. V., Serrill, J. D., Proteau, P. J., Ganley, I. G., McPhail, K. L. and Ishmael, J. E. (2013).
Coibamide A Induces mTOR-Independent Autophagy and Cell Death in Human Glioblastoma Cells.
PloS one 8, pp. e65250