- Signal Transduction
- PI3K/PTEN Pathway
Senior Research Scientist, Saskatchewan Cancer Agency
Professor, Division of Oncology
Associate Member, Department of Biochemistry
B.Sc. (Hons) University of Manitoba (1984)
Ph.D. University of Manitoba (1988)
Receptor tyrosine kinase (RTK) overexpression is frequently observed in many human cancers and drives cell division and cell survival. One major pathway activated by these receptors is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. PI3K activity consists of a p110 catalytic protein that phosphorylates lipids that in turn activate Akt signaling. The p110 protein is stabilized and regulated by another protein, p85.
Regulation of PTEN
PTEN is a tumor suppressor protein that counteracts the PI3K pathway, since it is the lipid phosphatase that dephosphorylates PI3K lipid products. We have recently shown that the p85 protein that regulates p110-PI3K activity, also directly binds and positively regulates PTEN lipid phosphatase activity. Thus, p85 is a dual regulator of both the kinase and the phosphatase controlling lipid levels and the resulting Akt signaling. Our results have been developed into a model that explains the paradoxical phenotypes observed in transgenic mice containing reduced p110, PTEN and p85 levels. We are also pursuing experiments to further characterize the regulatory effects of p85 towards PTEN.
Regulation of Receptor Endocytosis and Down-regulation
We are studying mechanisms cells use to decrease receptor tyrosine kinase levels via uptake of cell surface receptors into cells (endocytosis) and degradation in lysosomal compartments. The p85 protein also binds to many activated RTKs and remains bound while receptors are taken up inside cells. We have found that p85 has GAP activity that regulates Rab5 and Rab4 GTPases. Rabs are important for the trafficking of RTK-containing vesicles during endocytosis, receptor deactivation and recycling back to the cell surface, and for receptor sorting for degradation. Defects in the Rab regulatory function of p85 are oncogenic. We are studying this new role for p85 and the effect of mutations within the GAP domain of p85 that have recently been discovered in human cancer samples. We are also studying receptor trafficking and using complementary strategies in an effort to enhance EGFR &/or ErbB2 degradation in breast cancer cells.
Metastasis Suppressor CREB3L1
We are characterizing the metastasis suppressor protein, CREB3L1, activated during the stressful conditions (low nutrients and low oxygen) present in tumors. This transcription factor represses the expression of genes involved in cell growth, cell survival, migration and invasion, and is lost in highly metastatic breast cancer cells.