How protein protection mechanisms aid breast cancer cell migration and other stories from our latest publications
Jens Rauch, Lan Nguyen, William Fitzmaurice
Monday, 06 October, 2014
Breast cancer is the leading cause of cancer death in women worldwide. In Ireland, breast cancer has become the second most common cancer with over 2,000 women diagnosed every year. With an estimated one in eight women affected by breast cancer in their lifetime, scientists are urgently trying to find new diagnostic and therapeutic strategies to combat this disease and improve patient outcome.
Breast cancers are often clinically classified based on the type of receptors they bear. These are proteins that reside on the cell surface responsible for relaying extracellular signals into the cell to trigger a responsive chain of events. A substantial proportion of breast cancer patients display high level of members of a receptor family called ErbB, which consists of four related receptors EGFR, Her2, Her3 and ErbB4. The ErbB receptor network has thus received a lot of attention from researchers and has been a major therapeutic target in breast cancer. Despite significant progress in the development of drugs, particularly those targeting EGFR and Her2, patients always experience relapse of the disease after an encouraging, but short, initial response.
In a collaborative study recently published in the leading international journal Science Signalling, SBI researchers and co-authors from King's College London, University of Zurich, The Weizmann Institute of Science (and others) have worked out another important piece of the ErbB puzzle and shed light on how the ErbBs receptors interact with each other to influence how breast cancer cells move. They found that a form of the receptor ErbB4, called CYT2, could protect its kin protein EGFR from being destroyed by the cellular destruction machinery by shielding EGFR from a destroyer protein known as E3 ligases. This protection mechanism helps breast cancer cells migrate more efficiently.
“This piece of mechanistic understanding allowed us to better map out the ErbB interactions to construct a predictive mathematical model for the network. The model enables us then to develop a systems-level view of how the network behaves under various perturbations even before we go to the lab”, said SBI Research Fellow Dr Lan Nguyen and Prof. Boris Kholodenko who were involved in the research.
“Our findings uncovered novel mechanisms that may influence the efficacy of EGFR-targeted therapy. Moreover, the effect of ErbB4 CYT2 on cell motility – a key feature enabling cancer cells invasion and metastasis – suggests that it could be a potential therapeutic target” said Prof. Tony Ng from King's College London who led the study.
The ErbB4 CYT2 variant protects EGFR from ligand-induced degradation to enhance cancer cell motility.
Kiuchi T, Ortiz-Zapater E, Monypenny J, Matthews DR, Nguyen LK, Barbeau J, Coban O, Lawler K, Burford B, Rolfe DJ, de Rinaldis E, Dafou D, Simpson MA, Woodman N, Pinder S, Gillett CE, Devauges V, Poland SP, Fruhwirth G, Marra P, Boersma YL, Plückthun A, Gullick WJ, Yarden Y, Santis G, Winn M, Kholodenko BN, Martin-Fernandez ML, Parker P, Tutt A, Ameer-Beg SM, Ng T.
Sci Signal. 2014 Aug 19;7(339):ra78. doi: 10.1126/scisignal.2005157.
One Hippo and many masters: differential regulation of the Hippo pathway in cancer.
Romano D, Matallanas D, Frederick DT, Flaherty KT, Kolch W.
Biochem Soc Trans. 2014 Aug 1;42(4):816-21. doi: 10.1042/BST20140030.
Why read this paper? This review summarises the Kolch and Matallanas group’s research on the pro-apoptotic signal mediated by the MST2/Hippo over the last decade.
Molecular mechanisms of asymmetric RAF dimer activation.
Jambrina PG, Bohuszewicz O, Buchete NV, Kolch W, Rosta E.
Biochem Soc Trans. 2014 Aug 1;42(4):784-90. doi: 10.1042/BST20140025.
Why read this paper? This review by Edina Rosta’s group at King’s College London in collaboration with scientists at UCD discusses how molecular dynamics (MD) simulations can be used to model conformational transitions of RAF kinase dimers. These long-time MD simulations can provide unique insights into atomistically detailed structural data of experimentally difficult to observe conformational changes that govern the activation processes.
SBI Director Prof. Walter Kolch, Dr Lan Nguyen and Carolanne Doherty discuss the research behind their recent Nature Cell Biology paper, 'Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling'.
Robustness and evolvability of the human signaling network.
Kim J, Vandamme D, Kim JR, Munoz AG, Kolch W, Cho KH.
PLoS Comput Biol. 2014 Jul 31;10(7):e1003763. doi: 10.1371/journal.pcbi.1003763. eCollection 2014 Jul.
Why read this paper? This paper by Kwang-Hyun Cho’s group in South Korea in collaboration with scientists from SBI deals with the question of how biological systems can be robust and at the same time allow for evolution of internal mutations and external environmental changes, focusing on the human signaling network and defining the evolutionary design principles and their implication for the identification of novel drug targets.
Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses.
Dobrzynski M, Nguyen LK, Birtwistle MR, von Kriegsheim A, Blanco Fernández A, Cheong A, Kolch W, Kholodenko BN.
J R Soc Interface. 2014 Sep 6;11(98):20140383. doi: 10.1098/rsif.2014.0383.
Why read this paper? This paper demonstrates how differences in the drug dose response between individual cells affect the overall response on the population level, and how this response can be synchronised. It may be of interest to those studying cell-to-cell variability as well as synthetic biologists designing dose response characteristics.
SBI Deputy Director Boris Kholodenko’s paper ‘Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance’ was Biochemistry Society Transactions most cited paper of 2013.
Competing to coordinate cell fate decisions: the MST2-Raf-1 signaling device.
Nguyen LK,Matallanas D, Romano D, Kholodenko BN, and Kolch W.
Cell Cycle (in press).
Why read this paper? This paper presents an in-depth perspective on how completely opposing biological decisions (cell growth and death) can be achieved by the same molecular apparatus: the integrated MST2-Raf-1 signalling network. It sheds light on the general question of how biochemical signalling pathways generate biological specificity and demonstrates how mathematical modeling can be a great aid in this quest.
Ubiquitin chain specific auto-ubiquitination triggers sustained oscillation, bistable switches and excitable firing.
Nguyen LK,Zhao Q, Varusai TM, Kholodenko BN.
IET Systems Biology (in press).
Why read this paper? This original research paper unveils the rich and versatile dynamical properties of ubiquitin signalling systems that are regulated by self-catalysed ubiqitination, a common regulatory motif occurring in cells.comments powered by Disqus