Control of Cell Signalling and Membrane Trafficking Pathways by Phosphoinositide Regulatory Networks.

Our cells are divided into distinct membrane-bound compartments some of which form essential pathways that transport cargo into and out of cells. These membrane trafficking pathways control key cellular processes including nutrient uptake, clearance of activated growth factor receptors, and the secretion of hormones and neurotransmitters. However our understanding of membrane trafficking systems remains incomplete. We are studying the control of membrane trafficking pathways by specialized signalling lipids named phosphoinositides. Phosphoinositides (PI) are essential lipids in cellular membranes that have important roles in cell growth and development. Defects in PI metabolism have been implicated in many human diseases including cancer, diabetes, and neurodegenerative disorders. It is vital that we understand how cells maintain and use these signalling molecules. Our research integrates cell biology, biochemistry, and genetic strategies to uncover roles for PI signalling in membrane trafficking and cell signalling pathways to understand how cells respond to cues in their environment, such as growth factors, nutrients, and stress. These studies are especially relevant to the biology of neurons, as defects in PI signalling result in neurological and neurodegenerative disorders including Down’s syndrome, Alzheimer’s disease, and Parkinson’s disease. Our long-term goal is to develop new therapeutics for the treatment of diseases caused by PI signalling and membrane trafficking defects.

The transmission of signals across the plasma membrane allows cells to sense their surroundings and mount responses to external cues. Accordingly, the plasma membrane is highly organized and undergoes dynamic remodelling by the delivery and removal of material via the secretory and endocytic pathways. Our research focuses on the control of cell signalling and membrane trafficking pathways by phosphoinositide (PI) kinase regulatory networks. PI kinase signalling networks impact on several key cellular processes including cell growth and survival, cell proliferation and differentiation, cell polarity and migration, and membrane trafficking pathways. Consequently, defects in PI kinase regulatory networks have been implicated in numerous human diseases including cancer, diabetes, and neurodegenerative disorders. It is vital that we understand how cells maintain and use these essential signalling molecules. We are currently undertaking multidisciplinary approaches–including cell biological assays, high-resolution microscopy, system-wide functional genomics and proteomics, and biochemical approaches–to make new discoveries into the regulation of PI kinase signalling and membrane trafficking networks. We expect that these investigations will reveal new insights into the complex regulatory processes that ensure the temporal and spatial specificity of membrane trafficking systems, including regulated exocytosis and endocytosis during neurotransmission. As such, we expect these studies will be particularly relevant to neuronal physiology, as defects in PI metabolism have been implicated in several neurological and neurodegenerative disorders including Down’s syndrome, Alzheimer’s disease, and Parkinson’s disease.

Specifically, we have uncovered a pathway for crosstalk between the plasma membrane (PM) and endoplasmic reticulum (ER) involving PI kinase signalling at ER-PM junctions. Our findings indicate that ER-PM crosstalk allows the ER to mount essential responses (calcium dynamics, protein and lipid biogenesis) to ensure the integrity of the PM even under membrane stress conditions. Another striking result is our finding that ER–PM crosstalk is essential for normal ER morphology and function. Loss of ER-PM junctions causes dramatic changes in ER organization and architecture, resulting in activation of ER stress response pathways. We are currently investigating the roles for ER-PM crosstalk in maintaining ER homeostasis, as well as PM domain organization. Recent findings have placed ER stress as a key component of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). We expect that ER-PM crosstalk may serve critical functions at nerve terminals, including membrane lipid and calcium dynamics that drive synapse biogenesis and function. We are investigating the impact that PM-ER membrane contacts have on ER homeostasis, as well as the membrane lipid dynamics that modulate exocytosis and endocytosis during neurotransmission.