On the relation between filament density, force generation, and protrusion rate in mesenchymal cell motility

Setareh Dolati, Frieda Kage, Jan Mueller, Mathias Müsken, Marieluise Kirchner, Gunnar Dittmar, Michael Sixt, Klemens Rottner*, Martin Falckea

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    16 Citations (Scopus)

    Abstract

    Lamellipodia are flat membrane protrusions formed during mesenchymal motion. Polymerization at the leading edge assembles the actin filament network and generates protrusion force. How this force is supported by the network and how the assembly rate is shared between protrusion and network retrograde flow determines the protrusion rate. We use mathematical modeling to understand experiments changing the F-actin density in lamellipodia of B16-F1 melanoma cells by modulation of Arp2/3 complex activity or knockout of the formins FMNL2 and FMNL3. Cells respond to a reduction of density with a decrease of protrusion velocity, an increase in the ratio of force to filament number, but constant network assembly rate. The relation between protrusion force and tension gradient in the F-actin network and the density dependency of friction, elasticity, and viscosity of the network explain the experimental observations. The formins act as filament nucleators and elongators with differential rates. Modulation of their activity suggests an effect on network assembly rate. Contrary to these expectations, the effect of changes in elongator composition is much weaker than the consequences of the density change. We conclude that the force acting on the leading edge membrane is the force required to drive F-actin network retrograde flow.

    Original languageEnglish
    Pages (from-to)2674-2886
    Number of pages213
    JournalMolecular Biology of the Cell
    Volume29
    Issue number22
    DOIs
    Publication statusPublished - 1 Nov 2018

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