Our aim is to understand the complex “forest” of cell surface proteins that orchestrate cellular function. We focus on platelets, the first aid kit of the bloodstream, and the endothelial cells that line our blood vessels, because of their critical roles in health and disease processes leading to heart attack and stroke.
Platelets and endothelial cells play essential roles in maintaining blood vessel integrity and in wound healing, but can also give rise to the initiation and progression of atherosclerosis, leading to heart attack and stroke. These cells possess an array of receptors and adhesion molecules that regulate their function in health and disease. The tetraspanins are a superfamily of transmembrane proteins that interact with and “organise” other cell surface proteins into membrane microdomains. Such partitioning of proteins into membrane microdomains is critical for processes such as cell signaling and adhesion. Indeed, the fundamental importance of tetraspanins is underlined by their expression throughout the animal, plant and fungal kingdoms. By identifying novel tetraspanin-associated proteins on platelets and endothelial cells, and characterizing their regulation within tetraspanin microdomains, we aim to identify new drug targets for the prevention and treatment of cardiovascular disease.
Our studies are heavily focussed on genetically modified platelets and primary endothelial cells, with some additional use of cell line models. The techniques that we employ include genomics and proteomics, molecular biology, functional assays for platelets and endothelial cells, and analyses of protein-protein interactions through advanced microscopy and biochemical methods.
- Rubinstein E, Charrin S and Tomlinson MG (2013) Organisation of the tetraspanin web. In Tetraspanins (Berditchevski F and Rubinstein E, eds), Springer, Dordrecht, pp.47-90
- Haining EJ, Yang J, Bailey RL, Khan K, Collier R, Tsai S, Watson SP, Frampton J, Garcia P and Tomlinson MG (2012) The TspanC8 subgroup of tetraspanins interacts with a disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression. Journal of Biological Chemistry 287:39753-39765
- Bailey RL, Herbert JM, Kabir K, Heath VL, Bicknell R and Tomlinson MG(2011) The emerging role of tetraspanin microdomains on endothelial cells. Biochemical Society Transactions 39:1667–1673
- Senis YA*, Tomlinson MG*, Ellison S, Mazharian A, Lim J, Zhao Y, Kornerup KN, Auger JM, Thomas SG, Dhanjal T, Kalia N, Zhu JW, Weiss A and Watson SP (2009)The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis. Blood 113:4942-4954
- Protty MB, Watkins NA, Colombo D, Thomas SG, Heath VL, Herbert JMJ, Bicknell R, Senis YA, Ashman LK, Berditchevski F, Ouwehand WH, Watson SP and Tomlinson MG (2009) Identification of Tspan9 as a novel platelet tetraspanin and the collagen receptor GPVI as a component of tetraspanin microdomains. Biochemical Journal 417:391-400
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