Research Project

Website: http://dynactome.mshri.on.ca/

Summary

Proteins are large molecules responsible for the function, regulation, and structure of cells. Canadian-led research over the last two decades has demonstrated that proteins interact with one another and assemble pathways and networks within cells, which account for cells’ sophisticated behaviour. According to Dr. Tony Pawson, Director of the Samuel Lunenfeld Research Institute at Toronto’s Mount Sinai Hospital, a key to understanding diseases such as cancer lies in investigating the dynamic changes in the cell’s protein interaction network.

Dr. Pawson, with his colleague and fellow molecular biologist Dr. Jeff Wrana, and University of Western Ontario biochemist Shawn Li, lead this project. 

The project team is mapping protein interactions within human cells in order to determine whether diseases such as malignant cancers result not only from specific changes to individual genes and proteins, but also from changes in the entire cellular network. The project draws on valuable earlier discoveries by the research team.

For example, Dr. Pawson was the first to show that proteins interact in a regulated way through specific domains - something that is crucial for normal cell organization but which cancer-causing oncoproteins take over. Dr. Wrana is a world leader in understanding a super family of proteins, called Transforming Growth Factor Beta (TGF-ß), which helps regulate growth and function of human cells through molecular pathways.

This project, drawing on collaboration in the United States and China, represents the first large-scale effort to map dynamic interactions. It may well lead to new proteomic and computational technologies as well as innovative cancer therapies.

This project includes integrated GE³LS research on ethical issues and guidelines relating to the cross-jurisdictional use of human tissue and genetic information. For more information, click here.

Significant Outcomes to Date

• A total of 11 patents have been filed from discoveries directly related to the Dynactome project. One of these patents has resulted in the creation of Dynemo Biosystems, with core services centered on use of the DyNeMo algorithm that employs microarray gene expression data to monitor, on a global network scale, changes in expression levels of interacting proteins.  The Dynemo algorithm can be used to predict the severity of a disease and drug-effectiveness prior to treatment.
• Partners in the Dynactome project have developed multiple important genomics resources:
  

  		- The Human ORFeome collection has a collection of full length ORFs now encompassing almost 13,000 human genes and is comprised of over 15,000 Gateway clones.
  		- The protein interaction database (I2D) contains over 450,000 source and predicted interaction, about 100,000 of which are from human sources.
  		- NAViGaTOR is a software package for visualizing and analyzing protein-protein interaction networks.
  		- The NetworKIN algorithm predicts kinase-substrate relationships for 123 kinases and 5515 substrates.
  		- NetPhorest contains 125 non-redundant classifiers for linear motifs for phosphorylation-dependent signalling and SMALI predicts linear motifs that are likely to bind SH2 domains.

• Developed qBIDS (quantitative analysis of Bidirectional Signaling) for mass spectrometry that can distinguish proteins from distinct cell types in a mixed population and employed this method to analyze Ephrin signalling (Science. 2009 Dec 11;326(5959):1502-9)
• Have tested greater than 100,000 protein-protein interactions using their LUMIER technology.
• The Dynactome project has produced over 60 direct publications since inception, 27 of which are in Cell, Science or Nature related journals (7 of the publications in the leading journal Cell, 1 in Nature and 5 in Science). In addition, a further 7 publications in Cell, Science or Nature have resulted from research indirectly related to outcomes or resources generated from this project.
• Dr. Pawson was awarded the prestigious Kyoto Prize for his work "Proposing and Proving the Concept of Adapter Molecules in the Signal Transduction" in 2008.
• In January 2010, Dr. Pawson was named Canada’s “Nation Builder of the Decade in Science” by The Globe and Mail.

Notable Publications

Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells.
Jørgensen C, Sherman A, Chen GI, Pasculescu A, Poliakov A, Hsiung M, Larsen B, Wilkinson DG, Linding R, Pawson T.
Science. 2009 Dec 11;326(5959):1502-9.

Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway.
Miller BW, Lau G, Grouios C, Mollica E, Barrios-Rodiles M, Liu Y, Datti A, Morris Q, Wrana JL, Attisano L.
Mol Syst Biol. 2009;5:315. Epub 2009 Oct 13.

Taylor, IW., Linding, R., Warde-Farley, D., Liu, Y., Pesquita, C., Faria, D., Bull, S., Pawson, T., Morris, Q., Wrana, JL.  2009.  Dynamic modularity in protein interaction networks predicts breast cancer outcome.  Nat Biotechnol 27(2): 199-204

Braun, P., Tasan, M., Dreze, M., Barrios-Rodiles, M., Lemmens, I., Yu, H., Sahalie, JM.,
Murray, RR., Roncari, L., de Smet, AS., Venkatesan, K., Rual, JF., Vandenhaute, J., Cusick, ME., Pawson, T., Hill, DE., Tavernier, J., Wrana, JL., Roth, FP., Vidal, M.  2009. An experimentally derived confidence score for binary protein-protein interactions.  Nat Methods 6(1): 91-7

Bakal, C., Linding, R., Llense, F., Heffern, E., Martin-Blanco, E., Pawson, T., Perrimon, N. 2008.  Phosphorylation networks regulating JNK activity in diverse genetic backgrounds.  Science 322(5900): 453-6

Filippakopoulos, P., Kofler, M., Hantschel, O., Gish, GD., Grebien, F., Salah, E., Neudecker, P., Kay, LE., Turk, BE., Superti-Furga, G., Pawson, T., Knapp, S.  2008.  Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.  Cell 134(5): 793-803

Traweger, A., Wiggin, G., Taylor, L., Tate, SA., Metalnikov, P., Pawson, T.  2008.  Protein phosphatase 1 regulates the phosphorylation state of the polarity scaffold Par-3. Proc Natl Acad Sci U S A. 105(30): 10402-7

Varelas X, Sakuma R, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, and Wrana JL.  2008. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10(7):837-48.

Defining the specificity space of the human SRC homology 2 domain.
Huang H, Li L, Wu C, Schibli D, Colwill K, Ma S, Li C, Roy P, Ho K, Songyang Z, Pawson T, Gao Y, Li SS.
Mol Cell Proteomics. 2008 Apr;7(4):768-84. Epub 2007 Oct 22.

Linding R, Jensen LJ, van Vugt MA, Jorgensen C, Miron IM, Diella F, Colwill K, Taylor L, Elder K, Metalnikov P, Nguyen V, Pasculescu A, Jin J, Park JG, Samson LD, Woodgett JR, Russell RB, Bork P, Yaffe MB, and Pawson T. 2007. Systematic discovery of in vivo phosphorylation networks.  Cell. 129:1415-26.

Lau KS, Partridge EA, Silvescu CI, Reinhold VN, Demetriou M, and Dennis JW.  2007. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.  Cell. 129:123-34.

Dupuy D, Bertin N, Venkatesan K, Tu D, Lee D, Rosenberg J, Svrzikapa N, Blanc A, Carnec A, Carvunis AR, Pulak R, Shingles J, Reece-Hoyes J, Hunt-Newbury R, Viveiros R, Mohler WA, Tasan M, Roth FP, Le Peuch C, Hope IA, Johnsen R, Moerman DG, Barabasi AL, Baillie D, and Vidal M. 2007. Genome-scale analysis of in vivo spatiotemporal promoter activity in Caenorhabditis elegans. Nat Biotechnol 25(6): 663-8.

Fujisawa K, and Wrana JL. 2007. The slit receptor EVA-1 coactivates a SAX-3/Robo mediated guidance signal in C. elegans. Science. 317(5846):1934-8.

Wells CD, Fawcett JP Traweger A, Yamanaka Y, Goudreault M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K, Starostine A, Metalnikov P, and Pawson  A.  2006.  Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells.  Cell. 123(3) pp535-48.

Liu BA, Jablonowski K, Raina M, Arce M, Pawson T, and Nash PD. 2006. The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling.  Molecular Cell. 22(6) pp851-68.