Network-based identification of feedback modules that control RhoA activity and cell migration

Journal of Molecular Cell Biology
Tae-Hwan KimKwang-Hyun Cho

Abstract

Cancer cell migration enables metastatic spread causing most cancer deaths. Rho-family GTPases control cell migration, but being embedded in a highly interconnected feedback network, the control of their dynamical behavior during cell migration remains elusive. To address this question, we reconstructed the Rho-family GTPases signaling network involved in cell migration, and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration. Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGF are regulated by a negative-feedback module composed of Src, FAK, and CSK. Interestingly, perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration, suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration, while Src inhibition might fail, depending on the genetic background of cells. Thus, this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-fami...Continue Reading

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Citations

Aug 31, 2016·Small GTPases·Joseph H R HetmanskiPatrick T Caswell
May 4, 2016·PLoS Computational Biology·Joseph H R HetmanskiPatrick T Caswell
Dec 23, 2017·Journal of Molecular Cell Biology·Le ZhangChuanwei Yang
Feb 24, 2018·Physical Biology·Cole ZmurchokLeah Edelstein-Keshet
Nov 6, 2018·Journal of Molecular Cell Biology·Xiaoyu SongXuebiao Yao
Dec 4, 2016·Biochemical Society Transactions·Joseph H R HetmanskiPatrick T Caswell
Oct 22, 2016·BMC Systems Biology·Sung-Hwan ChoKwang-Hyun Cho
Mar 16, 2017·Protoplasma·Tomáš Mazel
Feb 23, 2020·Biophysical Journal·Cole Zmurchok, William R Holmes
Mar 11, 2021·PLoS Computational Biology·Joseph H R HetmanskiPatrick T Caswell

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