MassIVE MSV000080751

Imported Reanalysis Dataset Public PXD003213

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

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Description

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. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Rac1 ; RhoA ; cell motility ; PAK inhibition ; bistable switches ; mathematical modelling

Contact

Principal Investigators:
(in alphabetical order) 		Alex von Kriegsheim, University of Edinburgh, N/A
Submitting User: ccms

Publications

Byrne KM, Monsefi N, Dawson JC, Degasperi A, Bukowski-Wills JC, Volinsky N, Dobrzy?ski M, Birtwistle MR, Tsyganov MA, Kiyatkin A, Kida K, Finch AJ, Carragher NO, Kolch W, Nguyen LK, von Kriegsheim A, Kholodenko BN.
Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.
Cell Syst. 2016 Jan 27;2(1):38-48. Epub 2016 Jan 27.

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