Nicholas Ktistakis

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Signalling pathways regulated by phosphatidic acid and phosphatidylinositol 3-phosphate

Signalling pathways regulate communication between and within cells and they play significant roles in physiological decisions governing cell fate. Changes in the genes encoding proteins of these signalling pathways can have wide-reaching problems on cellular health.

We are interested in cellular traffic and lipid signalling with special emphasis on pathways and proteins regulated by two simple lipid signals, phosphatidic acid (PA) and phosphatidylinositol 3-phosphate (PI3P). As it is currently understood, these signals are formed on discrete membranes in the cell and thus regulate important cellular functions such as growth and intracellular traffic.

Enzymes of the phospholipase D (PLD) family have been studied for over 40 years, yet the signalling pathways in which they are implicated are still a matter of debate and an intense focus of investigation, especially because PA can have a signalling as well as a structural/biosynthetic function in cells (Figure 1 - right).

My group is interested in the structure/function characteristics of the PLD enzyme, as well as in potential cellular targets of PA such as sphingosine kinase 1 (SK1).

We are also very interested in the regulation of autophagy by PI3P a lipid that can be formed in cells by several routes (Figure 2 - left). When cells encounter limited nutrients, especially amino acids, they initiate a catabolic pathway which digests endogenous proteins for generation of novel nutrients.

This pathway is termed autophagy (self-eating) and it appears to be important for healthy ageing and life span extension whereas its miss-regulation is a causative or enhancing factor in many diseases. Our recent work has shown how formation of PI3P is important for the initiation of autophagy.