Background:

BSc Physiology and Biochemistry, University of Southampton; PhD Biochemistry, University of Southampton; Postdoctoral Research Fellow, University of Oxford; Postdoctoral Research Fellow, Harvard University; Lecturer, University of Southampton; presently Senior Lecturer in Biochemistry and Molecular Biology, University of Southampton.

Research Interests:

A molecular understanding of the cellular mechanisms of insulin and growth factor action will contribute enormously to our understanding of diabetes and cancer and should ultimately lead to the design of efficacious drug interventions. There are several major thrusts to current research. One is to elucidate insulin signalling pathways. A second is concerned with understanding signalling mechanisms in cancer and the development of novel anti-cancer drugs. A third is concerned with the molecular control of apoptosis. The roles of a variety of protein kinases, including protein kinase B (also called Akt), the atypical protein kinase Cs and MAP kinase (ERK1/ERK2) and are being studied. A range of cellular and molecular biological approaches are being employed. In particlular, we are at the forefront of using antisense technology as a novel way of elucidating cell signalling pathways and in the development of a new class of therapeutic agents.

Research Projects:

Elucidation of insulin signalling pathways
Insulin has many effects on cells. These range from stimulating cells to take up glucose from the blood, thereby lowering blood glucose, to affecting metabolism inside the cell and controlling events within the nucleus of the cell, which determines whether specific proteins are produced. How insulin achieves these effects is not fully understood, but understanding the process is fundamental to understanding diabetes (particularly non-insulin dependent diabetes mellitus) and the development of improved treatment methods. The broad aim of this project is to elucidate how insulin stimulates cells to take up glucose, how insulin controls metabolism and how insulin controls gene expression in the nucleus. A major recent innovative advancement in my laboratory has been the establishment of a new method for elucidating signalling events in single living cells, namely, the application of fluorescence correlation spectroscopy. Fluorescence correlation spectroscopy was applied to elucidate one of the most important actions of insulin, namely, how insulin stimulates the uptake of glucose from the blood. The studies identified 80K-H as new player in insulin signalling of glucose uptake and showed how a protein called munc18c regulates GLUT4 vesicle trafficking and glucose uptake. This resulted in the proposal of a major new model for how insulin signals glucose uptake. Funder: Diabetes UK.

Role of protein kinase B in signalling cancer
Breast cancer is the most common cancer in women and is increasing in both the developed and developing countries. There is an urgent need to understand the precise mechanisms of tumour development, to develop new treatment strategies and to identify predictive markers for tumour aggressiveness and therapy resistance. Recent research has shown that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathway is frequently dysregulated in cancer. The goal of this work is to define the role of PKB and its individual isoforms in signalling breast cancer. This work is timely because we have recently developed new tools for studying PKB, offering a unique opportunity to provide insight into the role of signalling by individual PKB isoforms in breast cancer cells. This study may also identify clinically relevant markers of disease and provide the necessary intellectual framework for the development of PKB-isoform selective inhibitors (e.g., antisense oligonucleotides, small chemical inhibitors) as novel therapeutic agents. Funder: Breast Cancer Campaign

Commercialization of PKB antisense oligonucleotides as anti-cancer drugs
Developing new and improved cancer treatment therapies is of crucial importance. A protein called protein kinase B (PKB, also known as Akt) has been shown to be a critical player in signalling of many major cancers, including breast, ovarian, lung, pancreatic, prostate, stomach and melanomas. We have developed and patented specific antisense agents to eliminate PKB and its isoforms from cells and demonstrated proof-of-principle that these antisense molecules act as potent anticancer agents. In this project we are now developing these antisense agents as anti-cancer drugs. Funder: BBSRC.

Molecular control of apoptosis
Understanding the molecular mechanism of apoptosis is of wide ranging importance because it constitutes the major form of physiological cell death and because suppression or induction of apoptosis contributes to or underlies many disease states. Protein kinase B (also called Akt) has recently been implicated as a key regulator protein that controls apoptosis. This project is concerned with dissecting the role of protein kinase B and its isoforms (α, β and γ) in preventing apoptosis and elucidating the targets and signal transduction pathways involved. Funder: BBSRC.

Collaborative projects
Various collaborative projects are underway. These are utilizing novel technologies generated in our laboratory, particularly, antisense technologies and the development of novel backbone structures to improve the efficacy of the antisense agents.

Selected Publications:

Smithers, N.P., Hodgkinson, C.P., Cuttle, M. and Sale, G.J. (2008) Insulin triggered repositioning of munc18 on syntaxin-4 in GLUT4 signalling. Biochem J. 2008 410, 255-260

Sale , E.M. and Sale, G.J. (2008) Protein kinase B: signalling roles and therapeutic targeting. Cell Mol Life Sci. 2007 65, 113-127

Sale , E.M., Hodgkinson, C.P., Jones, N.P. and Sale, G.J. (2006) A New Strategy for Studying Protein Kinase B and its Three Isoforms. Role of Protein Kinase B in Phosphorylating Glycogen Synthase Kinase-3, Tuberin, WNK1 and ATP Citrate Lyase. Biochemistry 45, 213-223

Mander, A., Hodgkinson, C.P. and Sale, G.J. (2005) Knock-Down of LAR Protein Tyrosine Phosphatase Induces Insulin Resistance. FEBS Lett. 579, 3024-3028

Hodgkinson, C.P., Mander, A. and Sale, G.J. (2005) Protein kinase C Zeta Interacts with Munc18c: Role in GLUT4 Trafficking. Diabetologia 48, 1627-1636

Hodgkinson, C.P., Mander, A. and Sale, G.J. (2005) Identification of 80K-H as a Protein Involved in GLUT4 Vesicle Trafficking. Biochem. J. 388, 785-793

Hodgkinson, C.P., Sale, E.M. and Sale, G.J. (2002) Characterization of PDK2 Activity Against PKB γ. Biochemistry 41, 10351-10359.

Hodgkinson, C. P. and Sale, G. J. (2002) Regulation of both PDK1 and the Phosphorylation of PKC-zeta and - delta by a C-Terminal PRK2 Fragment. Biochemistry 41, 561-569.

Arnott, C.H., Sale, E.M. Miller, J. and Sale, G.J. (1999) Use of An Antisense Strategy to Dissect the Signalling Role of Protein Tyrosine Phosphatase alpha. J. Biol. Chem. 274, 26105-26112

Yarwood, S.J., Sale, E.M., Sale, G.J., Houslay, M.D., Kilgour, E. and Anderson, N.G. (1999) Growth Hormone-Dependent Priming of Differentiation of 3T3-F442A Preadipocytes Requires Janus Kinase/Signal Transducer and Activator of Transcription but not MAP Kinase or p70 S6 Kinase Signalling Whereas Terminal Differentiation Requires MAP Kinase Signalling J. Biol. Chem. 274, 8662-8668.

Glennon, P.E., Kaddoura, S., Fuller, S.J., Sale, E.M., Sale, G.J. and Sugden, P.H. (1995) Induction of the Hypertrophic Phenotype in Cultured Ventricular Myocytes by Phenylephrine is Inhibited by Antisense Oligodeoxynucleotides Directed Against Mitogen-activated Protein-kinases. Circulation 92, 1116-1116

Sale, E.M., Atkinson, P.G.P. and Sale, G.J. (1995) Requirement of MAP Kinase for Differentiation of Fibroblasts to Adipocytes, for Insulin-Activation of p90 S6 Kinase and for Insulin- or Serum-Stimulation of DNA Synthesis. EMBO. J. 14, 674-684.

Patents

UK Patent: Use of antisense agents against protein kinase B as potential anti-cancer drugs

PCT Patent: Antisense molecules against protein kinase B/Akt as potential anti-cancer agents

Updated July 2009