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Dr. Deborah Anderson

Dr. Deborah Anderson
Director of Research and 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

Cunningham CE, Li S, Vizeacoumar FS, Bhanumathy KK, Lee JS, Parameswaran S, Furber L, Paul JM, Templeton SD, Shukla H, Boyd F, Alli N, Mousseau D, Geyer R, Bonham K, Anderson DH, Yan J, Yu-Lee L-Y, Weaver BA, Uppalapati M, Ruppin E, Sablina A, Freywald A and Vizeacoumar FJ (2016) Therapeutic relevance of the protein phosphatase 2A in cancer. Oncotarget. 2016 Sep 20;7(38):61544-61561. PMID: 27557495

Paul JM, Toosi B, Vizeacoumar FS, Bhanumathy KK, Li Y, Gerger C, El Zawily A, Freywald T, Anderson DH, Mousseau D, Kanthan R, Zhang Z, Vizeacoumar FJ and Freywald A (2016) Targeting synthetic lethality between SRC kinase and the EPHB6 receptor may benefit cancer treatment.  Oncotarget. 2016 Aug 2;7(31):50027-50042. PMID: 27418135

Beyrakhova KA, van Straaten K, Li L, Boniecki MT, Anderson DH and Cygler M (2016) Structural and functional investigations of the effector protein LpiR1 from Legionella pneumophila. J Biol Chem. 2016 Jul 22;291(30):15767-77. PMID: 27226543

Ward AK, Mellor P, Smith S, Kendall S, Just NA, Vizeacoumar FS, Sarker S, Phillips Z, Alvi R, Saxena A, Vizeacoumar FJ, Carlsen SA, and Anderson DH (2016) Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers.  Breast Cancer Res. 2016 Jan 25;18(1):12. PMID: 26810754

Satram-Maharaj T, Nyarko JNK, Kuski K, Fehr K, Truit L, Freywald A, Lukong E, Anderson DH and Mousseau DD (2014) The monoamine oxidase-A inhibitor clorgyline promotes features supporting an apparent mesenchymal-to-epithelial transition in the MDA-MB-231 breast cancer cell line. Cellular Signalling, Aug 22; 26(12):2621-2632. PMID: 25152370

Allonby O, El Zawily AM, Freywald T, Mousseau DD, Chlan J, Anderson D, Benmerah A, Sidhu V, Babu M, DeCoteau J and Freywald A (2014) Kinase-dead EphB6 receptor loses Hsp90 aid and is efficiently downregulated following stimulation.  Cellular Signalling, Aug 23; 26(12):2645-2657. PMID: 25152371

Grishin AM, Cherney M, Anderson DH, Phanse S, Babu M and Cygler M (2014) NleH defines a new family of bacterial effector kinases.  Structure, 22, 250-259. PMID: 24373767

Ross RL, Burns JE, Taylor CF, Mellor P, Anderson DH and Knowles MA (2013) Identification of mutations in distinct regions of p85 alpha in urothelial cancer. PLoS One, 8, e84411. PMID: 24367658

Mellor P, Deibert L, Calvert B, Bonham K, Carlsen SA and Anderson DH (2013) CREB3L1 is a metastasis suppressor that represses expression of genes regulating metastasis, invasion and angiogenesis.  Mol Cell Biol, 33, 4985-4995. PMID: 24126059

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. PMID: 23345407

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. PMID: 22305891

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. PMID: 22168437

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. PMID: 20570729

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.  PMID: 20505341

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. PMID: 20463066

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. PMID: 20212113

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.

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