Regulation of glucose uptake by insulin
We are primarily interested in the molecular basis by which insulin stimulates glucose uptake into fat and muscle cells. We know that the activation of the protein kinase, Akt (also known as PKB), is central to this effect of insulin, but it is unclear how this kinase controls the trafficking and fusion machinery involved in the insertion of GLUT4 into the plasma membrane. We are currently focusing on the role of Rab proteins and the Rab-binding proteins Rip11 and TBC1D1/4. Our studies involve a broad range of techniques including advanced cell biology (time-lapse confocal microscopy, TIRF, EM), proteomics and genome wide analyses.
Protein kinase signalling in lung cancer and glioma
The dysregulation of protein kinase signalling is fundamental to many different types of cancer. We are interested in how receptor tyrosine kinases such as the EGF receptor and IGF/insulin receptors drive tumour cell growth and migration, via the regulation of the downstream protein serine/threonine kinases Akt and GSK3 and their substrate proteins. We are also developing sensitive methods to monitor the activity of these kinases in very small biopsies of tumours and how this information could be used to target treatment with selective small molecule protein kinase inhibitors. All our studies involve the use of cell lines and freshly isolated human tumours samples, and collaborations with oncologists, surgeons and pathologists.
Doug Elder, Fred Boal, Elaine Thomas, Sam Reed, Lorna Hodgson, Colette How.
Hers I, Wherlock M, Homma Y, Yagisawa H, Tavaré JM. (2006) Identification of p122RhoGAP (deleted in liver cancer-1) serine-322 as a substrate for protein kinase B and RSK in insulin-stimulated cells. Journal of Biological Chemistry. 281: 4762-4770.
Welsh GI, Leney SE, Lloyd-Lewis B, Wherlock M, Lindsay AJ, McCaffrey M, Tavaré JM. (2007) Rip11 is a Rab11 and AS160-RabGAP binding protein required for insulin-stimulated glucose uptake in adipocytes. Journal of Cell Science. 120: 4197-4208.
Hill EV, Hudson CA, Vertommen D, Rider MH, Tavaré JM. (2010) Regulation of PIKfyve phosphorylation by insulin and osmotic stress. Biochemical and Biophysical Research Communications. 397: 650-655.
Welsh GI, Hale L, Eremina V, Jeansson M, Bek M, Lennon R, Pons D, Owen R, Satchell S, Miles M, Caunt C, McArdle C, Herzenberg A, Toth T, Pavenstädt H, Tavaré JM, Kahn CR, Mathieson P, Quaggin SE, Saleem M, Coward R. (2010) Insulin sensitivity of the kidney podocyte is critical for glomerular function. Cell Metabolism. 12: 329-340.
Vincent EE, Elder DJE, Thomas EC, Phillips L, May M, Morgan C, Pawade J, Sohail M, Hetzel MR, Tavaré JM. (2011) Evaluation of Akt phosphorylation on Thr308 and Ser473 as biomarkers of Akt protein kinase activity in human cancer: correlation of the phosphorylation of Thr308, but not Ser473, with Akt activity in vivo. British Journal of Cancer. 104: 1755-1761.
Leney SE, Tavaré JM. (2009) The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets. Journal of Endocrinology. 203:1-18.
Hers I, Vincent EE, Tavaré JM. (2011) Akt signalling in health and disease. Cell Signalling. 23(10): 1515-1527.