Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches

Kate m. Byrne; Naser Monsefi; John Dawson; Andrea Degasperi; Jimi-carlo Bukowski-wills; Natalia Volinsky; Maciej Dobrzyński; Marc r. Birtwistle; Mikhail a. Tsyganov; Anatoly Kiyatkin; Katarzyna Kida; Andrew J. Finch; Neil O. Carragher; Walter Kolch; Lan k. Nguyen; Alex von Kriegsheim; Boris n. Kholodenko

doi:10.1016/j.cels.2016.01.003

Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches

Kate m. Byrne, Naser Monsefi, John Dawson, Andrea Degasperi, Jimi-carlo Bukowski-wills, Natalia Volinsky, Maciej Dobrzyński, Marc r. Birtwistle, Mikhail a. Tsyganov, Anatoly Kiyatkin, Katarzyna Kida, Andrew J. Finch, Neil O. Carragher, Walter Kolch, Lan k. Nguyen, Alex von Kriegsheim, Boris n. Kholodenko

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Abstract / Description of output

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 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.

Original language	English
Pages (from-to)	38-48
Journal	Cell Systems
Volume	2
Issue number	1
Early online date	27 Jan 2016
DOIs	https://doi.org/10.1016/j.cels.2016.01.003
Publication status	E-pub ahead of print - 27 Jan 2016

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Alex Von Kriegsheim
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Cancer Network Biology
- Edinburgh Cancer Research Centre
Person: Academic: Research Active

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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, 2(1), 38-48. Advance online publication. https://doi.org/10.1016/j.cels.2016.01.003

@article{6a0dd525f7384c7ea808ca99901fdbbe,

title = "Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches",

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 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.",

author = "Kate m. Byrne and Naser Monsefi and John Dawson and Andrea Degasperi and Jimi-carlo Bukowski-wills and Natalia Volinsky and Maciej Dobrzy{\'n}ski and Marc r. Birtwistle and Mikhail a. Tsyganov and Anatoly Kiyatkin and Katarzyna Kida and Finch, {Andrew J.} and Carragher, {Neil O.} and Walter Kolch and Lan k. Nguyen and {von Kriegsheim}, Alex and Boris n. Kholodenko",

note = "This work was supported by the EU Seventh Framework under projects PRIMES (Grant No. FP7-278568), SynSignal (Grant No. 613879), and Breast Cancer NOW (2013NovPR183). We would like to thank Olivier Pertz (Basel) for the LifeAct, Mike Olson (Beatson) for the GST-Rhotekin, and Piero Crespo (Santander) for GST-PAK-CRIB constructs",

year = "2016",

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doi = "10.1016/j.cels.2016.01.003",

language = "English",

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journal = "Cell Systems",

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Byrne, K, Monsefi, N, Dawson, J, Degasperi, A, Bukowski-wills, J, Volinsky, N, Dobrzyński, M, Birtwistle, M, Tsyganov, M, Kiyatkin, A, Kida, K, Finch, AJ, Carragher, NO, 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

TY - JOUR

T1 - Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches

AU - Byrne, Kate m.

AU - Monsefi, Naser

AU - Dawson, John

AU - Degasperi, Andrea

AU - Bukowski-wills, Jimi-carlo

AU - Volinsky, Natalia

AU - Dobrzyński, Maciej

AU - Birtwistle, Marc r.

AU - Tsyganov, Mikhail a.

AU - Kiyatkin, Anatoly

AU - Kida, Katarzyna

AU - Finch, Andrew J.

AU - Carragher, Neil O.

AU - Kolch, Walter

AU - Nguyen, Lan k.

AU - von Kriegsheim, Alex

AU - Kholodenko, Boris n.

N1 - This work was supported by the EU Seventh Framework under projects PRIMES (Grant No. FP7-278568), SynSignal (Grant No. 613879), and Breast Cancer NOW (2013NovPR183). We would like to thank Olivier Pertz (Basel) for the LifeAct, Mike Olson (Beatson) for the GST-Rhotekin, and Piero Crespo (Santander) for GST-PAK-CRIB constructs

PY - 2016/1/27

Y1 - 2016/1/27

N2 - 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 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.

AB - 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 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.

U2 - 10.1016/j.cels.2016.01.003

DO - 10.1016/j.cels.2016.01.003

M3 - Article

SN - 2405-4712

VL - 2

SP - 38

EP - 48

JO - Cell Systems

JF - Cell Systems

IS - 1

ER -

Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches

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Alex Von Kriegsheim

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