Title:   
Senior Scientist

Institute:
University Health Network / Ontario Cancer Institute, Toronto

Department:  
Medical Biophysics / Signaling Biology

Province:
Ontario

Research interests:
Calcium Signalling and Related Signal Transduction Systems in Normal and Cancer Cells: Structure to Function 

Research Projects

Project title: 
Structural mechanisms of the Lfc oncogene regulation

Funding period:  
2010-2012

Program:
Operating Grant (Basic Research)

Summary:
This proposal investigates an enzyme that controls the way a cell is shaped and the way it moves. We have discovered this enzyme called Lfc, which plays a role in a large pathway of information flow that is important in cancer initiation and/or progression. Lfc turns on the molecular switch which is made of another protein called RhoA. When this molecular switch is on, it can stimulate cells to survive under low nutrient conditions and induce cells to grow, change shape and become motile. We employ a methodology called NMR, which enables detection of atoms within the enzyme and its interacting partners. Using this sophisticated methodology, we can monitor the Lfc enzymatic reaction in a real-time under various conditions which mimic cellular environments. We have recently discovered that a molecule called Tctex-1 can bind to Lfc and inhibits the Lfc function. We will endeavor to discover the mechanism underlying this inhibitory effect and hope to characterize the nucleotide exchange activity of Lfc under various physiological conditions including those found in cancer cells.
 

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Project title: 
Structural investigation on Ras Signaling and regulatory mechanisms

Funding period:  
2011-2013

Program:
Operating Grant (Basic Research)

Summary:
The Rat sarcoma (Ras) small G-protein is a signal transduction protein which enables cells to communicate ‘biological signals’ from outside to the nucleus. Certain mutations in ras genes can permanently activate Ras, which can result in the incorrect propagation of intracellular signals. Such disregulated Ras signaling can ultimately lead to tumor growth and metastasis. Indeed, approximately 30% of all human tumors contain activating mutations in Ras. In pancreatic cancer this figure goes up to 95% followed by 55% in thyroid cancer.  In this research proposal we hope to gain deeper insights into the mechanism of Ras-mediated signal transduction by using a technique called high-resolution nuclear magnetic resonance (NMR) spectroscopy. With this technique we can now measure the biological activity of Ras and its oncogenic mutants more accurately.  We will seek an innovative way to attenuate the hyperactivity of mutant Ras based on our detailed biochemical and structural analysis of the Ras signaling.

Past CRS projects:

2009 NMR investigation on Ras Signaling and regulatory mechanisms
 
2007 Structure and function of Rheb in mTOR signaling and oncogenesis
 
2005 Structural investigation on acute myeloid leukemia
 
2002 In vivo detection of protein-protein interactions
 
1999 Structural analysis of protein-protein interactions involved in oncogenesis.
 
1996 Structural studies of general transcription factor TFIID Interaction with p53 and VP16.

1994 Structural Basis for Tumour Suppression by the Retinoblastoma Protein