Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insu ....Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP-2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins, regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the long term may facilitate better treatment strategies for diabetic patients.Read moreRead less
Analysis Of The C-terminal Hypervariable Region Of Ras Proteins
Funder
National Health and Medical Research Council
Funding Amount
$419,241.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutrali ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutralise Ras function in these tumours is potentially enormous. Our previous work demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras gets to and attaches to the cell membrane. Once we understand this mechanism drugs can be designed to block Ras getting to the membrane. Such drugs should neutralize the effect of Ras in tumours and control cell proliferation. In fact, our previous study has already led to the identification of the first generation of anti-Ras drugs that work on this principle.Read moreRead less
Identification And Characterization Of Novel PI3-kinase Signal Transducing Elements In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-ki ....Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-kinase (PI3-kinase) and its lipid products PtdIns(3,4,5)P3 and PtdIns(3,4)P2. However, very little is known about exactly how PI3-kinase and its products regulate the platelet responses. Our research studies aim to gain a deeper understanding into the molecular mechanisms of PI3-kinase signal transduction in platelets, through the identification and characterization of novel platelet proteins that bind to PI3-kinase lipid products, and to define what role these proteins play in platelet PI3-kinase dependent responses.Read moreRead less
The Role Of Plasma Membrane Microdomains In Regulating Ras-dependent Raf Activation
Funder
National Health and Medical Research Council
Funding Amount
$216,100.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras attaches to and interacts with specific sites in the plasma membrane. Its is becoming clear that different isoforms of Ras, called H-, N- and K-ras have different functions in the cell which may in turn result from their different sites of attachment to the cell membrane. This is important because by understanding the precise micro-environment in which the different Ras proteins operate and how they activate subsequent proteins in their signaling networks we will be in a good position to design drugs that selectively compromise the function of each specific Ras isoform. A highly relevant example is provided by K-ras which is mutated in 90% of all pancreatic cancers and 50% of all colon cancers. Clearly the clinical impact of a drug that could selectively neutralise K-Ras function in these tumours is potentially enormous.Read moreRead less
Ras Signalling And Cholesterol Efflux From Late Endosomes
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Accumulation of cholesterol is a hallmark of early atherosclerotic lesions, known as foam cell formation. Hence the stimulation of cholesterol removal (efflux) from macrophages has great therapeutic potential. High Density Lipoproteins (HDL) and apolipoprotein A-I (apoA-I) stimulate efflux via activation of HDL-apoA-I receptors and poorly understood signalling pathways. This application is investigating the role of the Ras-MAPK signalling pathway in promoting efflux from late endosomes.
Functional Characterization Of Caveolae And Caveolins
Funder
National Health and Medical Research Council
Funding Amount
$140,660.00
Summary
This project aims to study the cellular machinery that allows a cell to respond to its external environment. Specifically, this project focusses on the function of a family of membrane proteins, called caveolins, which are the major protein components of caveolae small pits which cover the surface of many mammalian cells. Caveolins are believed to regulate signalling from the external environment to the cell interior and loss of this regulation leads to uncontrolled growth leading to cancer. Sig ....This project aims to study the cellular machinery that allows a cell to respond to its external environment. Specifically, this project focusses on the function of a family of membrane proteins, called caveolins, which are the major protein components of caveolae small pits which cover the surface of many mammalian cells. Caveolins are believed to regulate signalling from the external environment to the cell interior and loss of this regulation leads to uncontrolled growth leading to cancer. Signalling from the cell surface relies on organisation of signalling components into modules. Our studies suggest that these modules are dependent on specific lipid molecules which form discrete patches, called lipid rafts, on the cell surface. We have hypothesised that caveolins control the lipid molecules associated with lipid rafts and so, indirectly, control signalling pathways. In particular, we have shown that caveolin is important in the regulation of cellular cholesterol, a vital molecule involved in maintaining the function of lipid raft domains. As numerous human diseases are associated with cholesterol imbalance, studies of caveolins can give fundamental new insights into this process, and the previously unidentified links between the cellular lipid balance and signal transduction. This project aims to use mutant caveolin molecules to disrupt caveolin function and so determine the role of caveolin in lipid regulation and in signal transduction. We will then use a lower vertebrate model system, which is amenable to experimental manipulation, to determine the role of caveolins and rafts in the development of the whole embryo.Read moreRead less