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Dr. Deborah Anderson (Senior Research Scientist)

Dr. Deborah Anderson
Senior Research Scientist
Saskatchewan Cancer Agency
Professor, Division of Oncology
Associate Member, Department of Biochemistry

Location:
Cancer Cluster
Room 4D30.2 Health Science Building
107 Wiggins Road
University of Saskatchewan
Saskatoon, SK S7N 5E5
Phone: 306-966-7038
E-mail: deborah.anderson@saskcancer.ca

Research Interests

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.

Selected Publications

Basquin C, Malardé V, Mellor P, Anderson DH, Meas-Yedid V, Olivo-Martin J-C, Alice Dautry-Varsat and Sauvonnet N (2013) The signalling factor PI 3-kinase is a specific regulator of the clathrin-independent dynamin-dependent endocytosis of IL-2 receptors. J Cell Sci, 126:1099-108.

Meng S, Zhang M, Pan W, Li Z, Anderson DH, Ge B and Wang C (2012) Tyrosines 303/343/353 within the Sprouty-related domain of Spred2 are essential for its interaction with p85 and inhibitory effect on Ras/ERK activation.  Int J Biochem Cell Biol, 44, 748-758.

Mellor P, Furber LA, Nyarko JNK, and Anderson DH (2012) Multiple Roles for the p85a Isoform in the Regulation and Function of PI3K Signalling and Receptor Trafficking. Biochem J, 441, 23-37.

Chamberlain MD, Oberg JC, Furber LA, Poland SF, Hawrysh AD, Knafelc SM, McBride HM and Anderson DH (2010) Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking. Cell Signalling 22, 1562-1575.

Anderson DH (2010) p85 plays a critical role in controlling flux through the PI3K/PTEN signaling axis through dual regulation of both p110 (PI3K) and PTEN. Cell Cycle, 9, 2055-2056. 

Li Y, Lu X, Li J, Bérubé N, Giest K-L, Liu Q, Anderson DH, and Zhou Y (2010) Genetic engineered, biarsenical labelled influenza virus allows visualization of viral NS1 protein in living cells. J. Virol, 84, 7204-7213.

Chagpar RB, Links PH, Pastor MC, Furber LA, Hawrysh AD, Chamberlain MD and Anderson DH (2010) Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.  Proc Natl Acad Sci USA, 107, 5471-5476.

Torres VA, Mielgo A, Barila D, Anderson DH and Stupack D (2008) Caspase 8 promotes peripheral localization and activation of Rab5. J. Biol. Chem., 283, 36280-36289.

Li Y, Anderson DH, Liu Q and Zhou Y (2008) Mechanism of influenza A virus NS1 protein interaction with the p85b, and not the p85a, subunit of PI3K and upregulation PI3K activity.  J. Biol. Chem., 283, 23397-23409.

Chamberlain MD, Chan T, Oberg JC, Hawrysh AD, James KM, Saxena A, Xiang J and Anderson DH (2008) Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3`-kinase results in cell transformation.  J Biol Chem, 283, 15861-15868.

Shin Y-K, Li Y, Liu Q, Anderson DH, Babiuk LA and Zhou Y (2007) SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signalling pathway activation. J. Virol. 81, 12730-12739.

Dai Y, Wei Z, Sephton CF, Zhang D, Anderson DH, Mousseau DD (2007) Haloperidol induces the nuclear translocation of phophatidylinositol 3`-kinase to disrupt Akt phosphorylation in PC12 cells.  J Psychiatry Neurosci, 32, 323-330.

Ignatiuk A, Quickfall JP, Hawrysh AD, Chamberlain MD and Anderson DH (2006) The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3`-kinase and effect PDGF receptor down-regulation. J. Biol. Chem., 281, 5956-64. 

Anderson DH (2006) Role of Lipids in the MAPK signalling pathway. Progress in Lipids Research, 45, 102-119.

Selvakumar P, Lakshmikuttyamma A, Anderson DH and Sharma RK (2005) Molecular cloning, expression, purification and characterization of calcineurin from bovine cardiac muscle. Biochimie. 87, 975-983.

Anderson DH, and Chamberlain MD (2005) Assay and stimulation of the Rab5 GTPase by the p85a subunit of phosphatidylinositol 3-kinase. Methods in Enzymology, 403, Chapter 48, 552-561.

Chamberlain MD, and Anderson DH (2005) Measurement of the Interaction of the p85a subunit of phosphatidylinositol 3-kinase with Rab5.  Methods in Enzymology, 403, Chapter 47, 541-552.

Mahon ES, Hawrysh AD, Chagpar RB, Johnson LM, and Anderson DH (2005) A-Raf associates with and regulates platelet-derived growth factor receptor signalling.  Cellular Signalling, 17, 857-868.

Johnson LM, James KM, Chamberlain MD, and Anderson DH (2005) Identification of key residues in the A-Raf kinase important for phosphoinositide lipid binding specificity.  Biochemistry, 44, 3432-3440.

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