Lan Nguyen (Monash University)
Friday 20th May, 2016
ESJ King Theatre, Medical Building, The University of Melbourne
Tight coordination of the activity of Rho-family GTPases has been known to be essential for cell migration and it has been shown that two members of the family, RhoA and Rac1 mutually inhibit each other. The consequence of this double-negative feedback loop is a strict spatio-temporal separation of their activities. Using an integrated systems biology approach that combines predictive mathematical modelling and extensive wet-lab experimentation in MDA-MB-231 mesenchymal breast cancer cells, we construct a data-validated mathematical model of the Rac1/PAK/RhoA network. The model predicts that Rac1 and RhoA interactions via the p21-activated family kinases (PAK) can produce bistable, switch-like responses to a graded PAK inhibition. Model simulations also suggest that across a physiological range of parameter values, PAK inhibition would be the perturbation most likely to reveal bistable, switch-like behaviour of Rac1 and RhoA activity. We subsequently verify these model predictions experimentally. Using a small chemical inhibitor of PAK we confirm the predictions, demonstrating that cellular RhoA and Rac1 activation levels respond in a bistable manner to PAK inhibition where for a given inhibition dosage, these activity levels are high or low depending on the history of the system. Surprisingly, we demonstrate that downstream signalling, actin dynamics and cell migration also behave in a bistable fashion, displaying abrupt switches and hysteresis in response to PAK inhibition. In summary, our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that results in bistability, not only at the molecular level, but, intriguingly, also at the cellular level. These findings provide a tractable dynamic and mechanistic description of a biological phenomenon that is well described but still poorly understood. Moreover, breaking the Rac1/RhoA feedback by inhibiting PAK could switches the Rac/RhoA balance from a high Rac1-GTP to a high RhoA-GTP and which in turn could arrests actin polymerisation and migration in breast cancer cells, opening a new therapeutic avenue to treat invasive breast cancer.
Dr Lan Nguyen studied Applied Mathematics and Computing at Lincoln University (New Zealand) under the competitive New Zealand Study Award. He was soon introduced to the mysteriously wonderful world of cell biology and became deeply interested in interdisciplinary research that integrates cell biology and mathematical modelling. He went on to complete PhD in Computational Systems Biology early 2010 under Prof. Don Kulasiri at Lincoln, funded by the NZ TEC’s Top Doctoral Achiever scheme. He then joined Systems Biology Ireland (SBI), a leading systems biology institute in Europe, to carry out postdoc research under the mentorship of Profs Boris Kholodenko and Walter Kolch who are leading researchers in modelling and signal transduction. Dr Nguyen became a group leader at SBI in 2014. In Sep 2015, he joined Monash University as Head of a new Integrated Network Modelling Laboratory in the Dept. of Biochemistry & Molecular Biology and the newly established Biomedicine Discovery Institute.
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