Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insu ....Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP-2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins, regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the long term may facilitate better treatment strategies for diabetic patients.Read moreRead less
Regulation Of PtdIns(3,4,5)P3 By Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5- ....Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5-phosphatases. We propose the 5-phosphatases are essential for normal cell growth. Several studies have suggested in their absence tumour formation may occurr. We have identified a new member of this enzyme family called SHIP-2. This proposal aims to investigate the mechanisms by which this enzyme family metabolises signalling molecules and thereby regulates cell growth. We will also characterize how the 5-phosphatases control the normal pathways by which primitive cells differeniate into mature cells.Read moreRead less