Defining The Role And Contribution Of Cdc37 To Signal Transduction And Tumourigenesis By Src-family Kinases
Funder
National Health and Medical Research Council
Funding Amount
$411,430.00
Summary
Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade ....Cells respond to extracellular stimuli, such as growth factors and hormones, by activating intracellular networks of signaling molecules. It is the activation of these signaling networks that is ultimately responsible for mediating the biological responses of cells to extracellular stimuli (e.g. insulin stimulating glucose metabolism by cells). Members of the Src-family of tyrosine kinases are paramount among signaling molecules, as they are able to directly initiate the activation of a cascade of signaling networks that regulate the activity of the cell. Significantly though, the inappropriate activation of Src-family kinases has been implicated in the development of cancer, particularly breast and colon cancer, in humans. To fulfill their signaling functions however, Src-family kinases must first be folded into an active conformation upon their synthesis in the cell then be maintained in this conformation. Although previous studies, including our own, have implicated a class of proteins called molecular chaperones in this process, little is known about how the folding of Src-family kinases by these proteins is achieved and regulated. The overall aim of this study is to determine how the folding of Hck, one member of the Src-family of tyrosine kinases, into a conformation that enables it to participate in signaling networks is achieved and regulated. It is expected that the results from this study will provide significant new insight into how this process might influence the ability of cells to respond to extracellular stimuli and potentially contribute to the conversion of a normal cell into one with tumourigenic properties. Findings from this project may be particularly important in the context of human cancer. A better knowledge of how the signaling activity of Src-family kinases is regulated by molecular chaperones might provide a new avenue of investigation for the identification of novel chemotherapeutic agents.Read moreRead less
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
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