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 C.
AU - Degasperi, Andrea
AU - Bukowski-Wills, Jimi-Carlo
AU - Volinsky, Natalia
AU - Dobrzynski, 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, Alexander
AU - Kholodenko, Boris N.
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.
KW - Rac1
KW - RhoA
KW - cell motility
KW - PAK inhibition
KW - bistable switches
KW - mathematical modeling
UR - http://www.ncbi.nlm.nih.gov/pubmed/27136688
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 -
