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
Regulation Of The Tumour Suppressor PTEN By Phosphorylation And Oligomerization
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
The tumour suppressor PTEN is an enzyme involved in controlling cell growth, cell death, and cell migration. PTEN was identified as a tumour suppressor because many tumour cells were found to carry mutations in the PTEN gene that cause the loss of PTEN protein or the loss of PTEN enzyme activity. Hereditary mutations of the PTEN gene are the causes of a rare genetic disease called Cowden's disease. Cowden's disease patients are predisposed to developing skin, thyroid, and breast cancers. In labo ....The tumour suppressor PTEN is an enzyme involved in controlling cell growth, cell death, and cell migration. PTEN was identified as a tumour suppressor because many tumour cells were found to carry mutations in the PTEN gene that cause the loss of PTEN protein or the loss of PTEN enzyme activity. Hereditary mutations of the PTEN gene are the causes of a rare genetic disease called Cowden's disease. Cowden's disease patients are predisposed to developing skin, thyroid, and breast cancers. In laboratory conditions, increasing the abundance of PTEN in tumour cells such as brain and prostate tumour cells can suppress their growth, hence its role as a tumour suppressor. In addition to its role as a tumour suppressor, PTEN controls cancer cell spreading. Although much is known about the involvement of PTEN in cancer formation and the spreading of cancer cells, how PTEN suppresses tumour cell growth and spreading is not fully understood. The enzyme activity of PTEN enhances the removal of a chemical group called phosphate group from proteins and the fat-soluble compounds called phospholipids in the cell membrane. The ability of PTEN to suppress cell growth and spreading is due to its enzyme activity. However, exactly how the enzyme activity of PTEN is regulated is not well understood. In order for PTEN to efficiently enhance the removal of phosphate group from specific cellular proteins and phospholipids, PTEN needs to be located in close vicinity to these proteins and phospholipids. However, exactly how PTEN moves to the locations where these proteins and phospholipids are present remains elusive. This proposal aims at studying the regulation of PTEN enzyme activity and movement inside the cells. Results of the proposed studies will shed new light on how PTEN gene mutations contribute to cancer formation and the spreading of cancer cells and may facilitate the search for the cure of cancers.Read moreRead less