Bistability in the Rac1, PAK and RhoA signalling network is a feature of cell motility.

ABSTRACT: Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modelling and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that Rac1 and RhoA interactions via the PAK-family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK we confirm the model conjecture demonstrating that cellular RhoA and Rac activation levels respond in a bistable manner to PAK inhibition where for a given inhibition level these levels are high or low depending on the history of the system. Consequently, we show 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 mediates bistable GTPase activity and cell migration switches.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Mammary Gland Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Alex von kriegsheim  

LAB HEAD: Alex von Kriegsheim

PROVIDER: PXD003213 | Pride | 2016-12-23

REPOSITORIES: Pride