The regulated movement of membrane receptors and ligands between the cell surface and intracellular compartments is vital to many cellular operations, including communication between cells and their environment. However, the molecular details of these sorting events remain poorly defined. Determination of the mechanisms that control the cellular distribution of receptors is critical for understanding normal cellular processes and in pathological processes like tumorigenesis.
Role Of Conformational Change In Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that the primary event in signalling is the ability of the hormone to bring two receptors together (receptor dimerization). However, it may be that the receptor already is dimerized, and the role of the hormone is to induce a specific change in shape of the receptor, which transfers the signal of hormone binding into the cell to initiate signalling to the genome. We have good evidence that a specific shape change is required for activation of an important signalling pathway by growth hormone, and the closely structurally related receptor for erythropoietin is already dimerized before hormone binds. We want to find out exactly how the shape change acts, and whether the receptor is predimerized. This information is vital for designing small orally active mimics of growth hormone which could be of great value as an anabolic supplement for the frail elderly.Read moreRead less
Structural Studies On Cell Signalling Via The LIF Receptor And Gp130
Funder
National Health and Medical Research Council
Funding Amount
$453,943.00
Summary
The cytokines play important roles in the immune system during blood cell development and inflammation, and in nerve growth, bone remodeling, reproduction and heart development. Cell responses are initiated by a cytokine bringing together on the cell surface a receptor complex made up of multiple molecules. This project will investigate the atomic structure of the cell surface macromolecular complex, and hence the underlying mechanism by which cytokine signals are initiated.
Fluorescence Analysis Of The EGFreceptor Signalling Network
Funder
National Health and Medical Research Council
Funding Amount
$490,750.00
Summary
Receptors are cell-surface molecules that enable the cell to receive chemical messages from the outside environment and transmit these signals to the inside of cell. These messages tell the cells to grow, divide or die. The Epidermal Growth Factor Receptor is linked to a variety of cell signalling pathways that are critical to the normal functioning of cells. Conversely, abberations in Epidermal Growth Factor-mediated cell signalling leads to many types of cancers. A basic understanding of how t ....Receptors are cell-surface molecules that enable the cell to receive chemical messages from the outside environment and transmit these signals to the inside of cell. These messages tell the cells to grow, divide or die. The Epidermal Growth Factor Receptor is linked to a variety of cell signalling pathways that are critical to the normal functioning of cells. Conversely, abberations in Epidermal Growth Factor-mediated cell signalling leads to many types of cancers. A basic understanding of how the receptor is turned off or on is essential to designing drugs that can specifically inhibit its hyperproliferative response. High resolution structures of a key part of the Epidermal Growth Factor Receptor have identified several structural forms of the receptor that are providing valuable clues as to the structural basis for receptor activation. Armed with this information and advanced microscopic imaging technology we are in the unique position to probe receptor activation in living cells. This project seeks to determine which structural form of the receptor is responsible for transmission of cellular messages and how it is impaired in cancerous cells.Read moreRead less
A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
Tumor Specific Variants Of The EGFR: Characterization, Function And Target For Immunotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$140,880.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. This therapeutic approach requires an antibody that specifically binds to cancer cells but not normal cells. In this proposal, we wish to test a novel antibody that binds to a protein on the cell surface called the EGF receptor. While the EGF receptor is found on the surface on many cells, our antibody recognizes a modified version of the EGF receptor that is found exclusively on cancer cells. Previous EGF receptor antibodies tested in the clinic all recognized the normal EGF receptor and thus proved unsuitable as they bound to cells in the liver causing significant side effects. It is anticipated that the specificity of our novel antibodies will overcome this problem. Eventually this antibody could be used to treat patients with brain, breast, prostate and lung cancer. We will also conduct a number of studies to determine the function of this modified receptor. This work will improve our understanding of those events associated with development of tumors.Read moreRead less
Analysis Of Intracellular Signalling And Biological Activities Of The GM-CSF Receptor Family Using Constitutive Mutants
Funder
National Health and Medical Research Council
Funding Amount
$505,699.00
Summary
The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of th ....The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of the cytokine; importantly, the different mutants appear to trigger only a subset of the signals generated by the normal receptor. The aim of this project is to use our panel of constitutive beta subunit mutants to determine how the GM-CSF, IL-3 and IL-5 receptors generate signals inside the cell and how these signals lead to the various biological actions of the receptors on blood cell growth and maturation. Findings from this research will be relevant to the understanding and treatment of diseases which involve abnormal growth or function of blood cells such as leukaemia and inflammatory diseases.Read moreRead less