Michael Wakelam
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Systems biology of phosphatidic-acid-mediated signalling

Lipids are highly dynamic structures with both structural and signalling roles. To fully understand the roles that lipids have in cell function and in disease, we need the ability to follow their individual changes. In our lab we have pioneered the use of high-sensitivity liquid chromatography-mass spectrometry (LC-MS) technology to rapidly and comprehensively measure the levels of lipids in a wide range of cells, tissues and tumours. In particular our work focuses on understanding how phosphatidic acid, lyso-phosphatidic acid and phosphoinositides regulate a host of important cellular processes, such as membrane trafficking, secretion, adhesion, migration, survival, and replication. To achieve this aim our laboratory undertakes a multidisciplinary approach combining LC-MS analysis, with protein chemistry, cell biology, and genetic manipulation of model organisms (mouse, Drosophila melanogaster, Saccharomyces cerevisae, and Dictyostelium discoideum). In addition we are determining changes in cellular lipids in human diseases particularly cancer and type 2 diabetes.

Phosphatidic acid (PA) is a precursor to the synthesis of all cellular phospholipids. However, work in our laboratory using LC-MS, demonstrated that there exist distinct pools of phosphatidic acid that mediate phospholipid synthesis and intracellular signalling. Signalling phosphatidic acid is produced by the phosphorylation of diacylglycerol by particular members of a multigene family of diacylglycerol (DAG) kinase enzymes, and by the removal of the choline headgroup from phosphatidylcholine (PC), by two phospholipase D (PLD) enzymes. DAG kinase and PLD family members each have unique regulatory properties, intracellular localisations and cell-type expression. Therefore enabling cells a great deal of flexibility in how, and where, and in response to what stimulus, phosphatidic acid is generated to signal a specific process.

Lysophosphatidic acid is produced by autotaxin (ATX), a secreted lyso-PLD enzyme that removes the choline headgroup from lyso-phosphatidylcholine. LPA produced by ATX binds to specific cell surface receptors and regulates vascular function, cell proliferation, survival and migration. Distortion of ATX-dependent LPA signalling facilitates tumour progression by stimulating the formation of an invasive and/or angiogenic microenvironment for both malignant and stromal cells. We are defining the mechanisms adopted by tumour cells to regulate the release of ATX.

The principal aim of our laboratory is to understand how and where in cells, signalling phosphatidic acid is produced, and to identify the molecular targets and the cellular processes regulated by phosphatidic acid. Moreover, using the multidisciplinary approaches we employ and the collaborative research programmes pursued within the Babraham Institute, we intend to discover the complex inter-relationships between PA-mediated signalling, and LPA- and phosphoinositide-regulated signalling.