Figure 1

Plasticity of cell migration phenotypes and the core regulatory circuit.

(a) The phase diagram showing the Relationship between the activities of the GTPases and the plasticity of cell migration phenotypes. Background colors correspond to the different level of Rac1-GTP and RhoA-GTP - red for high level of Rac1-GTP, green for high level of RhoA-GTP, yellow for high levels of both of them and blue for low levels of both of them. The activity of the GTPases is hypothetically associated with the cell morphology and mobility. The phenotypes are depicted as cartoons displaying their corresponding morphological features - epithelial phenotype (E), hybrid epithelial-mesenchymal phenotype (E/M), mesenchymal phenotype (M), amoeboid phenotype (A) and hybrid amoeboid-mesenchymal phenotype (A/M). M phenotype is characterized with lamellopodia (LAM) and/or filopodia (FIL) and A phenotype here is specifically referred to Blebby amoeboid (BA) phenotype, which is characterized by blebbing. The A/M phenotype is considered as a set of different morphologies - Lamellipoida with blebs (LB), Lobopodia (LP) and Pseudopodal amoeboid (PA). The blue color is also associated with strong cell-cell adhesion, as observed in E or E/M phenotypes, while the rest colors are associated with single cell migration modes. (b) The core AMT/MAT regulatory circuit connected with the c-MET pathway. The AMT/MAT is mainly regulated by the Rac1/RhoA regulatory circuit, while RhoA and Rac1 are regulated via Grb2 and Gab1 by the c-MET pathway, which receives the external signal from HGF/SF. A solid arrow denotes activation and a solid bar stands for repression. A solid line represents transcriptional regulation and a dashed line is for non-transcriptional regulations such as GTP loading. (c) Dynamical system characteristics of the Rac1/RhoA regulatory circuit. The plot shows the nullclines and possible steady states corresponding to Equation (1). Without any external signal (Grb2 = 0, Gab1 = 0), the circuit can be tristable. Red nullcline is for d and black nullcline is for . Green solid circles denote the stable fixed points and green hollow circles denote the unstable fixed points. Each stable point can be associated with a cell phenotype, depicted as a cartoon beside them.