Quick Project Snapshot
Control of protein transport in exosomes by Ndfip1
Exosomes are secreted extracellular vesicles that carry proteins and nucleic acids for export. The contents of exosomes can be internalized by recipient cells with physiological and sometimes pathological consequences. We have discovered that Ndfip1 can control the loading of proteins for export. One important exosome passenger is PTEN, a tumour suppressor that is important for cancers in the breast, brain, prostate and skin. Without Ndfip1, the tumour suppressor PTEN fails to be exported. In this project, we will ask what factors are responsible for directing PTEN into exosomes, and how can these be harnessed to increased PTEN transport in exosomes for reducing tumours.
- Putz, U., Howitt, J., Lackovic, J., Foot, N., Kumar, S., Silke, J. and Tan, S-S (2008) Nedd4-family interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem 283:32621-32627
- Howitt, J., Lackovic, J., Low, L-H., Naguib, A., Macintyre, A., Goh, C-P., Callaway, J.K., Hammond V., Thomas, T., Dixon, M., Putz, U. Silke, J., Bartlett, P., Yang, B., Kumar, S., Trotman, L.C., Tan, S-S. (2012). Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia J. Cell Biol. 196:29-36
- Putz, U., Howitt, J., Doan, A., Goh, C-P., Low, L-H., Silke, J., Tan, S-S (2012)The tumor suppressor PTEN is exported in exosomes for phosphatase activity in recipient cells. Science Signaling 5:ra70
Exosome Biology Laboratory
Brain cells are in constant communication with each other for transmitting electrical and chemical signals during mental activity. However, we believe that certain chemicals are also exchanged between brain cells for purposes that are not related to sensory and motor activity, for example for brain repair after injury. Brain communication is also important for protection of nerve cells against brain stress. We are currently engaged in discovering the nature of these communications and the circumstances behind their transmission.
We have been engaged in studying this natural method of communication using vesicles called exosomes. The exchanged material contains important messages (proteins, nucleic acids) that can have important consequences for cells that receive them. For example, in cancer, the spread of cancerous cells can be either hastened or retarded depending on the nature of these messages. Recently, we found out how to include certain additional messages that are normally not found in these exosomes. We are excited to study how these new messages can be used to repair brain cells after injury by boosting levels of repair proteins. In addition, we are enthusiastic about using these exosomes for transferring anti-cancer messages into brain tumours for reversing cancerous growth.
All Projects by this LabInvestigating interneuron migration and placement into cortical circuitsControl of protein transport in exosomes by Ndfip1How can Ndfip1 reduce brain damage following stroke?How does the brain protect itself during injury?Protein trafficking in neurodegenerative diseases.
Brain Development & Regeneration
Our group is interested in the self-defence mechanisms that operate in the brain when something goes wrong. This may take the form of degenerative disease (Parkinson's, Alzheimer's) or cancer (brain tumours) due to gene mutations and ageing. As a result, mutant or toxic proteins accumulate in brain cells, causing them to degenerate or proliferate. We have been working with one system of self-defence called protein ubiquitination which allows harmful proteins in brain cells to be removed and in the process, halt or reverse the disease process. We are particularly interested in finding how to accelerate beneficial ubiquitination in neurones using the Nedd4/Ndfip1 proteins. Our studies so far demonstrate that these proteins can halt cell death following injury and stroke, and slow down the division of brain cancer cells.