Elucidation Of Signalling Enzymes Regulating The Small GTPase RhoA
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Many normal and pathological processes in the human body depend on the ability of cells to attach to a biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes that require such events include the division and arrangement of cells in a developing embryo, or the ability of cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability to rearrange a scaffolding called the cytoskeleton. The c ....Many normal and pathological processes in the human body depend on the ability of cells to attach to a biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes that require such events include the division and arrangement of cells in a developing embryo, or the ability of cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability to rearrange a scaffolding called the cytoskeleton. The cytoskeleton is similar to the skeleton of the human body, in that it acts to maintain cell shape and rigidity. However, it is also actively reorganised to participate in many cellular processes, including cell attachment and movement. By furthering our understanding of how the cytoskeleton is rearranged, this will provide important insights not only into the basics of cell behaviour, but will also have important implications for a number of human disease states. This proposal aims to investigate mechanisms that regulate the reorganisation of the cytoskeleton. It is well established that the rearrangement of this scaffolding, in many different types of cells, is controlled by a family of proteins called the Rho family of small GTPases. One of the members of this family, RhoA, has a specific role in controlling cell attachment, and interestingly, has been implicated in the invasive and metastatic properties of human tumour cells. We have recently identified a protein that is responsible for controlling the activation of RhoA. This proposal aims to further our understanding of how this protein regulates RhoA, and therefore cell attachment and movement. Given that cell attachment and movement are important events contributing to the spread of tumours, this study may provide important insight into alternative approaches of controlling cell movement, and ultimately malignant progression.Read moreRead less
The Role Of Protein Tyrosine Phosphatases Regulating Eph RTK-signalling And Modulating Invasive Tumour Cell Properties.
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they r ....The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they re-appear in many tumors. For example, when normal cells in the skin (melanocytes) become tumor cells, they often will have Ephs and ephrins on their surface. It is believed that these proteins will now affect if these melanoma cells will migrate and to which locations within the body. In our studies we will examine what controls the activity of Eph proteins. In particular, a class of enzymes called tyrosine phosphatases are known to regulate the function of tyrosine kinase receptors, however it is not clear which particular phosphatase regulates EphA3, the focus of our studies. We will find out, which set of phosphatases regulates EphA3 function and whether exposure to oxidative conditions, such as UV radiation, also activates Ephs and instructs tumour cells to become more motile and to invade other areas of the body. The understanding of this mechanism will help to understand the cause of cancers such as melanoma and might offer possibilities to optimise new strategies for its treatment.Read moreRead less
Myosin VI: A Novel Molecular Apparatus For Epithelial Cohesion
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Adhesion between cells holds the human body together and affects many aspects of our health including normal tissue and organ function. Conversely, loss of normal cell-cell adhesion contributes to major diseases, including cancer and inflammation. One key molecule, E-cadherin, is necessary for many epithelial organs and its function is perturbed in disease. This research project addresses how E-cadherin works with a cellular motor, Myosin VI, to maintain the integrity of epithelial tissues.
Adhesion between cells is important during health and disease. Cell-cell interactions are necessary both as the embryo forms and to preserve tissues and organs in later life. Important disease states arise when cell-cell adhesion is broken. Only by understanding the molecular mechanisms that hold cells together can we analyse how they are perturbed to cause diseases such as cancer and inflammation.
Preserving Barriers: How Cadherin Signaling Coordinates Dynamic Adhesion And Tight Junction Assembly In Epithelial Cell.
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Epithelia protect the body from its environment. Breakdown of the epithelial barrier in tissues such as the skin and intestine, as occurs in burns and inflammation, leads to invasion of bacteria and severe metabolic disturbances. In this project we study the cell signaling mechanisms that maintain epithelial barriers in healthy tissues that undergo turnover and remodelling. Understanding these signaling pathways provides a foundation to understand how they are perturbed in disease.
A Fluorescent Zebrafish Model Of Endodermal Cell Migration.
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
The most catastrophic event in cancer progression is when individual cancer cells move to other areas of the body and develop into secondary tumours. This very complex process shows striking similarities to cell movements during embryogenesis. In this project, we use a model system, the zebrafish, to analyse how cells move during embryogenesis. We will determine the genes required for cell movements in the zebrafish embryo, so we can find the corresponding genes in human cancers.
Cortactin: Integrating Cadherin Signalling For Junctional Integrity
Funder
National Health and Medical Research Council
Funding Amount
$593,888.00
Summary
Adhesion between cells holds the human body together and affects many aspects of our health, including normal tissue and organ function. Importantly, loss of normal cell-cell adhesion contributes to many diseases, including cancer and inflammation. One key adhesion molecule, E-cadherin, is necessary for many epithelial tissues and its function is perturbed in disease. This research project addresses how E-cadherin signals into cells to control cell-to-cell interactions.
Regulation Of Dynamic Cell-cell Adhesions By Coordinated Action Of Lipid Kinases And Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion i ....This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion is exemplified by the fact that disruption of cadherin adhesion contributes to many important diseases, especially inflammation and cancer. Thus understanding how cadherins hold cells together is necessary for us to understand the molecular basis of common diseases. In this project we study how cadherins signal to regulate cellular behaviour. We build on our recent discovery that E-cadherin can activate a lipid in the cell membrane, PIP3, that is known to be a key regulator of many cellular activities. We aim to understand how this signal is generated in response to E-cadherin adhesion and how it elicits normal cellular responses to cadherin adhesion.Read moreRead less