Regulation Of PtdIns(3,4)P2 Signalling By Inositol Polyphosphate 4-phosphatase-1
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. We have idenitified a novel enzyme called the inositol polyphosphate 4-phosphatase that appears to regulate cell proliferation and differentiation.
Characterization Of A Novel Regulator Of Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$592,235.00
Summary
PI3K is an enzyme required for new blood vessel formation during embryo development as well as in response to tumour formation. We have identified a novel enzyme that opposes PI3K signals and we hypothesise that it regulates new blood vessel formation in various physiological settings. We propose to investigate the role of this enzyme in blood vessels using mouse models in which this protein is reduced or absent.
Characterization Of The 72 KDa Inositol Polyphosphate 5-phosphatase
Funder
National Health and Medical Research Council
Funding Amount
$454,050.00
Summary
Cells respond to external signals and the enviroment to undergo cell growth, secretion and or other specialized functions including control of cell death and or cell size. We have identified a new enzyme (72 kDa 5-phosphatase) which resides inside the cell, which we have evidence plays a role in regulating both the movement of intracellular vesicles and also lipid signals stimulated by insulin. We have characterised the phospholipids that the enzyme cleaves and demonstrated the generation of new ....Cells respond to external signals and the enviroment to undergo cell growth, secretion and or other specialized functions including control of cell death and or cell size. We have identified a new enzyme (72 kDa 5-phosphatase) which resides inside the cell, which we have evidence plays a role in regulating both the movement of intracellular vesicles and also lipid signals stimulated by insulin. We have characterised the phospholipids that the enzyme cleaves and demonstrated the generation of new cell signals at specific subcellular localizations on intracellular membranes. We predict the generation of these specific lipid signals may play a significant role in controlling the transport of intracellular cargo to specific sites in the cell. In this grant proposal we aim to examine the regulation of specialised cargo called the glucose transporter, which is found in fat and muscle cells, and also the mannose 6-phosphate receptor, which regulates the trafficking of specific enzymes which mediate digestion of proteins. These studies include the clarification of which phospholipid signals the enzyme terminates and where in the cell this occurs. Secondly, we will examine the movement of the glucose transporter GLUT-4 in unstimulated cells and in response to insulin and furthermore how expression of the novel enzyme regulates its movement. We will also examine the movement of the mannose 6-phosphate receptor and the specific phospholipid signals which control the route the receptor traffics, using inhibitors of lipid signals and expression of lipid phosphatases and kinases. We will also examine how our novel enzyme forms complexes with other molecules in the cell and characterise these novel molecules using basic biochemical assessment of enzyme activity and function. Finally we will examine the regulation of intracellular messages by our novel enzyme following insulin stimulation, which facilitates glucose uptake into the cell.Read moreRead less
Identification And Characterization Of Novel PI3-kinase Signal Transducing Elements In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-ki ....Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-kinase (PI3-kinase) and its lipid products PtdIns(3,4,5)P3 and PtdIns(3,4)P2. However, very little is known about exactly how PI3-kinase and its products regulate the platelet responses. Our research studies aim to gain a deeper understanding into the molecular mechanisms of PI3-kinase signal transduction in platelets, through the identification and characterization of novel platelet proteins that bind to PI3-kinase lipid products, and to define what role these proteins play in platelet PI3-kinase dependent responses.Read moreRead less
The Role Of The Inositol Polyphosphate 4-phosphatase In Cellular Signalling
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to i ....Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to investigate the role of a specific lipid called PtdIns(3,4)P2 that recruits signalling proteins to specific cellular membranes including the inner wall of the plasma membrane and vesicles found within the cell. We have identified and are currently characterizing a novel enzyme called the inositol polyphosphate 4-phosphatase that terminates the signals generated by PtdIns(3,4)P2. We are characterizing mice which lack this enzyme. 4-phosphatase deficient mice demonstrate significant abnormalities in the brain and bone marrow. These mice appear unable to make circulating platelets, small anucleate cells which are vital in preventing bleeding. We will determine how the 4-phosphatase functions in regulating platelet production, by examining the bone marrow and blood of these mice. These studies are significant as platelet production is essential for prevention of blood loss following trauma and also is of vital importance in conditions associated with blood clotting including heart attack and stroke. Secondly we have identified a related enzyme to the 4-phosphatase designated P-Rex-1 which is highly expressed in brain and nerve cells. This proposal aims to determine if P-Rex-1 promotes nerve development.Read moreRead less
CHARACTERISATION OF A NOVEL REGULATOR OF PHOSPHOINOSITIDE 3-KINASE-MEDIATED CELL PROLIFERATION AND PLATELET SIGNALLING
Funder
National Health and Medical Research Council
Funding Amount
$500,091.00
Summary
Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to inf ....Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to influence other diverse functions, such as uptake of glucose, and blood clot initiation.Read moreRead less
Characterisation Of A Novel PI3-kinase Signal Terminating Enzyme In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$633,512.00
Summary
Breast cancer is the most common malignancy among females, affecting 1 in 9 women before the age of 85. Normally cells divide only when they receive a stimulus from a hormone or growth factor. The PI3K pathway which responds to these stimuli has been implicated in cancer where cells divide uncontrollably and invade surrounding tissue. We have identified a potential cancer suppressing gene, PIPP, which turns off PI3K growth signals. We aim to characterize the role of PIPP in breast cancer.
The Role Of PIPP In Cell Polarization And Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, P ....Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, PI3-kinase generates a molecule known as PtdIns(3,4,5)P3 which leads to the activation of many proteins in the signaling pathway. All cells which have PI3-kinase also have enzymes which act to switch off the signals generated by PI3-kinase and thus may play a role in preventing cancer and regulating cell development. We have identified a new enzyme known as PIPP and have shown that it acts to switch off the signals generated by PI3-kinase. We plan to investigate the role of PIPP by increasing or decreasing the amount of PIPP in cells and analysing the effects on cell growth and development. We have also identified a number of proteins which bind to PIPP and we will investigate the role these proteins play in regulating cell signaling. In addition, we plan to characterize the function of PIPP in a whole animal by generating mice which lack PIPP (knockout mice) and assessing the effects on development and cancer.Read moreRead less
The Role Of The 72 KDa Inositol Polyphosphate 5-phosphatase In Cellular Function.
Funder
National Health and Medical Research Council
Funding Amount
$549,196.00
Summary
Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of t ....Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of these PI3-kinase signals plays in the activation of the oncogene. In addition the levels of the 72kDa enzyme is altered in some cervical and lymphoma cancers. We will image live cells containing specific fluorescent probes under different conditions and study the activation and location of these probes in order to understand how different PI3-kinase signals are regulated in time and space. In addition to regulating signals that are involved in cancer, PI3-kinase controls signals that are important for proper immune function. Phagocytosis is a biological process where specialised immune cells (macrophages) take up and remove harmful particles such as bacteria or tumour cells from the circulation. This process depends on PI3-kinase and the signals it produces. We will determine whether the 72 kDa enzyme, which is expressed in macrophages, plays a role in regulating these signals during phagocytosis. We have shown that the 72 kDa enzyme can interact with several different proteins which may affect its location and activity within the cell. We will examine the effect of these interactions on the PI3-kinase signals which are involved in cell survival and immune responses. We will study the function of the enzyme in the intact animal by producing mice which lack this enzyme. Given the possible role of this enzyme in cancer, these mice will be examined for their susceptibility to develop tumours.Read moreRead less