Vordiplom Biologie, Friedrich-Schiller-Universitaet Jena, Germany, 1993

MSc Biochemistry, University of Dundee 1995

PhD, University of Cambridge 1999

Post-doc and senior post-doc, MRC LMCB, London and The Babraham Institute, Cambridge, 1999-2005

Group leader, The Babraham Institute, Cambridge, 2006-2012

MRC/UoE CIR, University of Edinburgh, 2013 to date 

Cellular signalling regulates diverse cellular responses including cell differentiation, growth, survival and migration, as well as specific functions of specialised cell types (e.g. neutrophil degranulation or production of reactive oxygen species). Depending on the situation their activation can result in different outputs. Examples for important signalling proteins include agonist-activated phosphoinositide 3-kinase (PI3K)  and small GTPases of the Ras superfamily (Ras, Rho, Arf etc). A typical cell has 25-50 different PI3K effectors, many of which are regulators of small GTPases, so-called guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that aid GTPase cycling between the inactive, GDP-bound and the active, GTP-bound state. There are many small GTPase family members who in turn regulate a number of effectors. Interestingly, the number of GEFs and GAPs far exceeds that of small GTPases. My lab studies how the cross-talk between PI3K and small GTPases contributes to regulation of complex physiological processes such as neutrophil chemotaxis / recruitment.

We work specialised cell types, such as the neutrophil, the most abundant peripheral blood leukocyte in man. Neutrophils provide the first line of defense against  infections. These short lived, terminally differentiated cell leave the blood stream following activation to travel to sites of infection or sterile insult where they phagocytose and kill pathogens, releasing reactive oxygen species and cytotoxic enzymes and generate inflammation. We are also interested in endothelial cells, specialised cells that line blood vessels. Endothelial cells perform a barrier function and are being crossed by neutrophils (and other leukocytes). During inflammation the endothelial barrier becomes leaky, causing swelling. Both transendothelial migration and leakyness are complicated processes that are regulated by cross-talk between endothelial cell and leukocytes. We are interested in the signalling processes involved, focussing once more on PI3K and small GTPases. Much of our current work centres around ARAP3, a PI3K and Rap regulated GTPase activating protein for Rho and Arf family small GTPases. ARAP3 was one of many PI3K effectors identified in a screen for PI3K effectors from pig neutrophils. We already showed that ARAP3 regulates endothelial cell biology (angiogenesis).  In the neutrophil, ARAP3 regulates chemotaxis and adhesion-dependent processes. We proposed that this is due to ARAP3-dependent modulation of the activity of leukocyte integrins. Our current questions are: How can the same enzymatic reaction lead to such different cellular read-outs in the two different cell types? What are the downstream effectors involved? How relevant are our observations for physiological situations in vivo?

Figure 1:

Neutrophils that did or did not contain ARAP3 were seeded onto glass and allowed to chemotax to a point source of chemoattractant. Cells were time-lapse imaged to visualize cell movement. In the stills shown, the movement of the individual cells was tracked. Control cells moved readily to the micropipette, whilst ARAP3-deficient did not. Stars show the original positions of the micropipette in the control field; this had to be moved to avoid the cells from crawling into the micropipette.

Julia Chu, PhD student

Ben Cathcart, PhD student