Alex Toker Lab

Alex Toker joined the faculty of Beth Israel Deaconess Medical Center and Harvard Medical School as an Assistant Professor in 2000. In 2003, he was promoted to Associate Professor and joined the faculty of the HMS Ph.D. program in Biological and Biomedical Sciences. Dr. Toker earned his B.A. from King's College, University of London, U.K. in 1987 and his Ph.D. from the National Institute for Medical Research, London. U.K. in 1991. He conducted his post-doctoral research first in the Department of Physiology, Tufts University School of Medicine, then in the Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center. His first faculty appointment was as Staff Scientist at the Boston Biomedical Research Institute in 1997, where he was promoted to Principal Scientist in 1999.

Research Interests

Research in the Toker laboratory focuses on the cell and molecular biology of carcinoma progression. Specifically, we are investigating the mechanisms by which several intracellular signaling pathways impact tumor cell survival, cell migration and cell invasion. The goal is to decipher the complex mechanisms by which these signaling pathways impact the behavior of cancer cells, with the ultimate goal of developing specific drugs which could interfere with the processes by which tumor cells become malignant and ultimately invade and metastasize to distant organs.

Lab Projects

A major research focus in the laboratory is the regulation of carcinoma cell migration and invasion, with emphasis on the signaling pathways which impact this phenotype. Work in our laboratory has focused on transcription factors of the NFAT (Nuclear Factor of Activated T cells) family. We have found that NFATs are expressed and functionally active in cancer cells, and that NFAT transcriptional activity is required for promoting carcinoma invasion (Jauliac, NCB 2002). The significance of these studies is that they afford insight into a gene, NFAT, not previously known as being important for human carcinoma invasion and metastasis, and may thus provide a novel approach for targeted drug design for anti-tumor therapies. More recent studies have focused on the role of the Akt proto-oncogene in modulating breast cancer progression. We have discovered that Akt1 is breast cancer cell motility and invasion suppressor, a surprising finding considering that the PI 3-K and Akt pathway is clearly implicated in tumor progression (Yoeli-Lerner, Mol. Cell 2005). The significance of these findings is that small molecule inhibitors of Akt, currently being developed by many pharmaceutical companies, may actually enhance tumor invasion and metastasis. We have also discovered that a secreted variant of ADAM9, termed ADAM9-S, a member of the A Disintegrin And Metalloprotease family of matrix metalloproteases, is expressed and secreted by stromal cells in the tumor microenvironment, and promotes tumor invasion (Mazzocca, Can. Res. 2005). The current focus is to gain additional insight into the role of NFAT, Akt and ADAM9-S in invasion and migration, as well as genome-wide screens for genes induced by these pathways in carcinoma cells and the use of animal modes of invasion and metastasis to determine the importance of these proteins in the progression of the disease.

Another major research focus in the laboratory is the function of the serine/threonine kinase PKD (protein kinase D) in cancer cell biology. Our studies have shown that PKD is critical for the activation of the transcription factor NF-kB, leading to increased cellular survival in response to mitochondrial oxidative stress (Storz et al, MCB 2005). The significance of these results is that they describe a signaling pathway which cells use to increase their survival capacity under conditions of oxidative stress. ROS have been implicated in numerous human pathologies, including cancer, inflammation, Parkinson's disease, and are also believed to be major causative factors in human aging. Current goals include analysis of the mechanisms by which PKD regulates cancer progression at the level of cell survival and invasive migration in breast and prostate cancer, and identification of specific PKD substrates and how they modulate these phenotypes. Thus, we have an active and long-term interest in kinase signaling and how it impacts downstream signaling pathways leading to cell growth, survival and motility.

Selected References

Original Articles

Thomas F. Franke, David R. Kaplan, Lewis C. Cantley and Alex Toker. Direct Regulation of the Akt Proto-Oncogene Product by PtdIns-3,4-P2. (1997) Science 275: 665-668. Medline.
Margaret M. Chou, Weimin Hou, Joanne Johnson, Lauren K. Graham, Mark H. Lee, Ching-Shih Chen, Alexandra C. Newton, Brian S. Schaffhausen and Alex Toker. Regulation of Protein Kinase Cz by PI 3-Kinase and PDK-1. (1998) Current Biology: 8: 1069-1077. Medline.
Toker, A. and Newton, A. C. Akt/PKB is Regulated by Autophosphorylation at the HypotheticalPDK-2 Site. (2000) Journal of Biological Chemistry. 275: 8271-8274. Medline.
Cenni, V., Döppler, H., Sonnenburg, E. D., Maraldi, N, Newton, A. C. and Toker, A. Regulation of Novel Protein Kinase C e by Phosphorylation. (2002) Biochemical Journal, 363: 537-545. Medline.
Jauliac, S., López-Rodriguez, C., Shaw, L. M., Brown, L. F., Rao, A. and Toker, A. The Role of NFAT Transcription Factors in Integrin-Mediated Carcinoma Invasion. (2002) Nature Cell Biology, 4: 540-544. Medline.
Storz, P. and Toker, A. Protein Kinase D Mediates a Stress-Induced NF-kB Activation and Survival Pathway. EMBO J. (2003); 22:109-120. Medline.
Storz, P., Döppler, H., and Toker, A. Protein kinase C delta selectively regulates protein kinase D-dependent activation of NF-kB in oxidative stress signaling. Mol. Cell Biol. (2004); 24 (7): 2614-2626. Medline.
Yoeli-Lerner, M., Yiu, G. K., Erhardt, P., Jauliac, S. and Toker, A. Akt/PKB blocks breast cancer cell motility and invasion through the transcription factor NFAT. (2005) Molecular Cell, 20: 539-550. Medilne
Mazzocca, A., Coppari, R., De Franco, R., Cho, J.-Y., Libermann, T., Pinzani, M. and Toker, A. A secreted form of ADAM9 promotes tumor invasion through tumor-stromal interactions. (2005) Cancer Research, 65 (11): 4728-4738. Medline
Storz, P., Döppler, H. and Toker, A. Protein Kinase D Mediates Mitochondria-to-Nucleus Signaling and Detoxification from mROS. (2005) Molecular and Cellular Biology, 25 (19): 8520-8530. Medline
Yiu, G. K. and Toker, A. NFAT Induces Breast Cancer Cell Invasion by Promoting the Induction of Cyclooxygenase-2. J. Biol. Chem., 2006; 281 (18): 12210-12217. Medline

Reviews

Alex Toker. Protein Kinases as mediators of Phosphoinositide 3-Kinase Signaling. (2000) Molecular Pharmacology. 57: 652-658. Medline.
Alex Toker and Alexandra C. Newton. Cellular Signaling: Pivoting Around PDK-1. (2000) Cell. 103: 185-188. Medline.
Peter Storz and Alex Toker. 3'-Phosphoinositide-Dependent Kinase-1 (PDK-1) in PI 3-K Signaling. (2002) Frontiers in Bioscience. 7: D886-902. Medline.
Toker, A. The Biology and Biochemistry of Diacylglycerol Signaling. EMBO Reports 2005; 6: 310-314. Medline
Toker, A. and Yoeli-Lerner, M. Akt/PKB Signaling and Cancer - Surviving but not Moving On. Cancer Research 2006, 66 (8): 3963-3966. Medline
Toker, A. Akt signaling: a damaging interaction makes good. Trends in Biochemical Sciences 2008; 33 (8): 356-359. Medline

Lab Folk