| Zdroj: |
Byrne, K, Monsefi, N, Dawson, J, Degasperi, A, Bukowski-wills, J, Volinsky, N, Dobrzyński, M, Birtwistle, M, Tsyganov, M, Kiyatkin, A, Kida, K, Finch, A J, Carragher, N O, Kolch, W, Nguyen, L, von Kriegsheim, A & Kholodenko, B 2016, ' Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches ', Cell Systems, vol. 2, no. 1, pp. 38-48 . https://doi.org/10.1016/j.cels.2016.01.003 |
| Popis: |
SummaryDynamic 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 modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demonstrate that cellular RhoA and Rac1 activation levels respond in a history-dependent, bistable manner to PAK inhibition. Consequently, we show that downstream signaling, actin dynamics, and cell migration also behave in a bistable fashion, displaying switches and hysteresis in response to PAK inhibition. Our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that governs bistable GTPase activity, cell morphology, and cell migration switches. |
