Huang, BinLu, MingyangJolly, Mohit KumarTsarfaty, IlanOnuchic, José NelsonBen-Jacob, Eshel2014-11-142014-11-142014Huang, Bin, Lu, Mingyang, Jolly, Mohit Kumar, et al.. "The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition." <i>Scientific Reports,</i> 4, (2014) Nature Publishing Group: 6449. http://dx.doi.org/10.1038/srep06449.https://hdl.handle.net/1911/78271Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of, and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.engArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.Journal articlecomputational modelscomputer modellingcancer modelshttp://dx.doi.org/10.1038/srep06449