Cortactin: Molecular Regulation Of Cadherin Activity And Epithelial Morphogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule E-cadherin is a major protein that controls how cells interact with one another in many epithelial tissues (e.g. breast, lung, gut). These tissues are the source of many common diseases, particular cancer and inflammation. E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to disease in these tissues (especially common ca ....Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule E-cadherin is a major protein that controls how cells interact with one another in many epithelial tissues (e.g. breast, lung, gut). These tissues are the source of many common diseases, particular cancer and inflammation. E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to disease in these tissues (especially common cancers, such as breast and lung). Understanding how E-cadherin controls normal cell function in these tissues will therefore provide key insights into how disease arises. In this study we will investigate how a protein which binds to E-cadherin, cortactin, contributes to the biological effect of E-cadherin in supporting tissue architecture. Understanding the fundamental elements of how cortactin works with E-cadherin will provide invaluable information into how cells recognize one another in health, and fail to adequately recognize each other in common diseases.Read moreRead less
How Caveolae Condition Tissue Mechanics For An Anti-tumor Niche.
Funder
National Health and Medical Research Council
Funding Amount
$1,091,226.00
Summary
The outcome of cancer is determined not only by the behaviour of the cancer cell, but also by how the normal tissue cells of the body respond to it. This project investigates how tissue cells that surround cancer cells can eliminate early cancers from the body. It develops on newly-discovered mechanisms that allow epithelial tissues to detect and physically expel cancer cells. This mechanism can protect us from cancer, but potentially allow cancer to develop when it fails.
Microtubule Capture By E-cadherin: A Novel Mechanism For Dynamic Cell-cell Adhesion.
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. It has long been known that cadherins work in cooperation with elements within the cell, called the cytoskeleton. My lab has recently made the novel discovery that microtubules, specific components of the cytoskeleton, can regulate the functionof cadherin adhesion molecules. Inparticular, microtubules appear to affect how cadherins can participate in dynamic cell processes necessary for cells to be properly organized in tissues. In this project we will probe the molecular mechanisms responsible for this effect of microtubules. The information obtained will provide important new insights into how dynamic cadherin adhesion is controlled, to help our understanding of the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.Read moreRead less
Preserving Junctions: Regulating Cadherins By Rho And Myosin 2.
Funder
National Health and Medical Research Council
Funding Amount
$425,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. Characteristically, cadherins accumulate in structures called adherens junctions, and preserving those junctions is important both for tissues to organize and also to prevent tumor progression. Despite this, we know very little about how junctions are preserved in epithelia. The research to be conducted in this grant will examine exactly this problem. It builds upon recent findings from my lab which indicate that the motor molecule, myosin 2 plays an essential role in preserving junctions. Furthermore, we will test the role for signaling pathways within cells to control the activity of myosin 2 at junctions. This research will provide important novel insights into the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.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.
E-Cadherin Endocytosis In Morphogenesis: Recycling And Growth Factor Induced Uptake.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell ....E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell surface E-cadherin serves to regulate its role in adhesion. More recently, we and others have shown that E-cadherin is endocytosed in response to growth factors, in conjunction with the activated growth factor receptors themselves. E-cadherin can influence the trafficking and signaling of these receptor tyrosine kinases. This joint endocytosis is an elegant mechanism for the simultaneous downregulation of cell adhesion and activation of signaling for cell growth and motility. The growth and differentiation of epithelial cells during tissue patterning or morphogenesis relies critically on these endocytic pathways. Our research is aimed at defining the endosomes and cellular machinery involved in E-cadherin-receptor endocytosis, moreover we will pursue initial findings suggesting that there are different pathways and fates for E-cadherin endocytosed at the behest of different growth factors. We will study endocytosis during the processes of epithelial cyst formation and tubulation of cysts as an in vitro model for mammalian morphogenesis. These studies will provide important and novel information for understanding the roles of E-cadherin in adhesion and in growth factor signaling during epithelial morphogenesis. Ultimately these findings will be of relevance to epithelial development and the prevention of cancer.Read moreRead less