한빛사 논문
Sung Hoon Lee1,2, Jay C. Hou3, Archer Hamidzadeh1,2, M. Sulaiman Yousafzai1,2,4, Visar Ajeti1,2,4,5, Hao Chang1,2, David J. Odde3, Michael Murrell1,2,4, Andre Levchenko1,2,6,*
1Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA
2Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
3Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA
4Department of Physics, Yale University, New Haven, CT 06520, USA
5Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA
*Corresponding author.
Abstract
Navigation through a dense, physically confining extracellular matrix is common in invasive cell spread and tissue reorganization but is still poorly understood. Here, we show that this migration is mediated by cyclic changes in the activity of a small GTPase RhoA, which is dependent on the oscillatory changes in the activity and abundance of the RhoA guanine nucleotide exchange factor, GEF-H1, and triggered by a persistent increase in the intracellular Ca2+ levels. We show that the molecular clock driving these cyclic changes is mediated by two coupled negative feedback loops, dependent on the microtubule dynamics, with a frequency that can be experimentally modulated based on a predictive mathematical model. We further demonstrate that an increasing frequency of the clock translates into a faster cell migration within physically confining spaces. This work lays the foundation for a better understanding of the molecular mechanisms dynamically driving cell migration in complex environments.
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