E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During development, E-cadherin is essential for establishing the cellular architecture of epithelial organs and for maintaining epithelial function in the adult. In this context, E-cadherin acts to establish and maintain the polarity of epithelial cells. E-cadherin is also a powerful tumour suppressor and the loss of E-cadherin expression or function is a primary event in metastasis and cancer in ....E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During development, E-cadherin is essential for establishing the cellular architecture of epithelial organs and for maintaining epithelial function in the adult. In this context, E-cadherin acts to establish and maintain the polarity of epithelial cells. E-cadherin is also a powerful tumour suppressor and the loss of E-cadherin expression or function is a primary event in metastasis and cancer invasion. Proteins at the surface of epithelial cells must be sorted and trafficked, or transported, to different membrane domains. E-cadherin, for instance, must be trafficked to the lateral domain of cells in order to function in cell-cell adhesion. We recently discovered that cell surface E-cadherin is re-internalized and recycled back to the surface via a pathway that is poised to contribute to the regulation of cell adhesion. Our proposed studies aim to reveal how newly-synthesized E-cadherin and recycling E-cadherin are trafficked, which molecules and which vesicle carriers accomplish this transport. E-cadherin has specific amino acids that act as targeting signals for its sorting and trafficking; we have recently identified one such signal and will now seek the signal responsible for its endocytosis. Using specifically engineered mutants of E-cadherin we will also study other proteins that interact with E-cadherin during its trafficking for sorting and regulation. One of these is polycystin, a protein that is mutated in a common inherited kidney disease. Insights into this disease and normal kidney epithelial function will emerge from this work. A growing understanding of E-cadherin function and regulation is essential for the health of epithelial organs and for controlling and preventing cancer.Read moreRead less
Prof Parton is a cell biologist studying how the plasma membrane functions in health and in disease. These studies have provided new insights into potential vehicles that can be used to introduce therapeutic agents into cells.
The Role Of Plasma Membrane Microdomains In Cellualar Function
Funder
National Health and Medical Research Council
Funding Amount
$4,083,868.00
Summary
The planned research program relates to novel hypotheses regarding the role of cell surface domains in organising signalling pathways at the cell surface. The proposal will involve identifying the domains and molecules involved in specific signalling pathways and dissecting the formation and function of surface structures called caveolae. The findings will have huge importance for therapeutic strategies aimed at combating the cellular changes associated with cell transformation in cancer and oth ....The planned research program relates to novel hypotheses regarding the role of cell surface domains in organising signalling pathways at the cell surface. The proposal will involve identifying the domains and molecules involved in specific signalling pathways and dissecting the formation and function of surface structures called caveolae. The findings will have huge importance for therapeutic strategies aimed at combating the cellular changes associated with cell transformation in cancer and other human diseases.Read moreRead less
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
The Regulation Of PI 3-kinase Second Messenger Molecules, PtdIns(3,4)P2 And PtdIns 3-P.
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been describ ....Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been described that have lost the ability to switch off PI 3-kinase signals. The current project aims to investigate a recently identified enzyme called the 4-phosphatase that has the ability to terminate PI 3-kinase signals. Recent studies have shown this enzyme regulates cell growth. In addition key experiments have shown the enzyme is important as it may regulate certain strains of bacterial infection. This research proposal aims to investigate how the enzyme works to regulate these growth promoting signals. This may help us develop novel therapeutic strategies to control cell growth.Read moreRead less
Molecular And Functional Characterisation Of Cell Surface Microdomains
Funder
National Health and Medical Research Council
Funding Amount
$4,803,731.00
Summary
This research program aims to gain a detailed understanding of the organisation of the cell surface at the molecular level. The cell surface is organised into domains with distinct functions. Visualisation of these domains, identifying their important components, and understanding how they form and function will have huge importance for therapeutic strategies aimed at combating the changes associated with cell transformation in cancer and in other human diseases such as muscular dystrophy.
Structure, Transport And Assembly Of PorB, A Key Invasion Molecule Of Meningococcal Disease
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
When the bacteria that cause meningococcal disease invade cells, they use specialized cell surface pore proteins to hijack the human cell and maintain infection. This research will study the structure of these bacterial pore proteins to help understand how they function to subvert normal cellular processes, and this insight will be important in the development of new treatments for meningococcal disease.
Remodelling Of Bacterial Outer Membranes: Implications For Vaccine Development.
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
We have identified proteins located in bacteria that are responsible for growth and the transport of essential nutrients. We will use a combination of bacterial genetics, protein biochemistry and immunological techniques to fully characterize these proteins. This strategic knowledge has direct implications for vaccine development and National security, since similar species of bacteria were amongst the first biological weapons.