Molecular Biology of Retinal Degenerations
Protein interaction machines in oncogenic EGF receptor signalling
Facts & Figures
- Duration: 5 years (12/20111-11/2016),
- Funding Agency: EU-FP7
PRIMES focuses on the role of protein interactions to assemble dynamic molecular machines that receive and process information to coordinate cellular responses. PRIMES investigates the following: (i) How do protein interactions contribute to the generation of biological specificity in signalling? (ii) How do pathogeneticperturbations affect protein interaction networks? (iii) How can we exploit protein interactions as therapeutic targets? We focus on the EGFR/ERBB signalling network and its role in colorectal cancer (CRC), the third most frequent cancer. The ERBB network is frequently altered in CRC either through overexpression or mutation of the receptors or downstream components. Network components have become important drug targets. Poor response rates and resistance demonstrate we lack sufficient insight to design efficacious therapies.
Using proteomics, structural biology, advanced imaging and mathematical modelling we (i) map static and dynamic protein interactions in the ERBB network (ii) unravel the design principles and emergent network properties conferred by protein interactions; and (iii) validate these findings in genetic mouse models of CRC and human tissues. PRIMES aims to (i) enhance the functional pathogenetic understanding of CRC (ii) identify mechanisms of drug resistance and drug efficacy; and (iii) identify drugs that affect protein interactions to rationally manipulate network functions related to individual genetic mutations.
Outcomes include (i) a dynamic, mechanistic flowchart of how protein interactions compute biochemical and biological specificity in signalling networks (ii) a functional protein interaction network of healthy and oncogenic ERBB signalling validated in mouse models of CRC and human tissues (iii) network level insights towards personalised CRC treatment based on genotype-phenotype relationships; and (iv) chemical compounds targeting protein interactions to restore normal ERBB network function or break oncogenic circuits.
- Walter Kölch, University College Dublin, Ireland (Coordinator)
- Boris Kholodenko, University College Dublin, Ireland
- Matthias Wilm, University College Dublin, Ireland
- David Lynn, Teagasc- Agriculture and Food Development Authority, Ireland
- Manfred Auer, University of Edinburgh, United Kindom
- Stefan Knapp, University of Oxford, United Kindom
- Owen Sansom, The Beatson Institute for Cancer Research, United Kindom
- Luis Serrano, Fundació Privada Centre de Regulació Genòmica, Spain
- Ivan Dikic, Johann Wolfgang Goethe-Universität, Germany
- Philippe Bastiaens, Max Planck Institut Dortmund, Germany
- Mathias Uhlén, Royal Institute of Technology, Sweden
- Ola Söderberg, Uppsala Universitet, Sweden
- György Kéri, Vichem Kémiai Kutató Kft., Hungary
- Igor Stagljar, The Governing Council of the University of Toronto, Canada
Scientists in Ueffing Lab
- Karsten Boldt
- Mohamed-Ali Jarboui
- Layal Dernayka
- Gloeckner, C. J., Boldt, K., Schumacher, A., Roepman, R. & Ueffing, M. A novel tandem affinity purification strategy for the efficient isolation and characterisation of native protein complexes. Proteomics 7, 4228-4234, doi:10.1002/pmic.200700038 (2007).
- Gloeckner, C. J., Boldt, K., Schumacher, A. & Ueffing, M. Tandem affinity purification of protein complexes from mammalian cells by the Strep/FLAG (SF)-TAP tag. Methods Mol Biol 564, 359-372, doi:10.1007/978-1-60761-157-8_21 (2009).
- Gloeckner, C. J., Boldt, K. & Ueffing, M. Strep/FLAG tandem affinity purification (SF-TAP) to study protein interactions. Curr Protoc Protein Sci Chapter 19, Unit19 20, doi:10.1002/0471140864.ps1920s57 (2009).
- Meixner, A. et al. A QUICK screen for Lrrk2 interaction partners--leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. Mol Cell Proteomics 10, M110 001172, doi:10.1074/mcp.M110.001172 (2011).