Feedback regulation by the RhoA-specific GEF ARHGEF17 regulates actomyosin network disassembly

Abstract

We report that the RhoA-specific guanine nucleotide exchange factor ARHGEF17 localizes at the back of a fibroblasts contractile lamella and regulates its disassembly. This localization emerges through retrograde ARHGEF17 transport together with actomyosin flow that most likely involves interactions with ATP-actin at F-actin barbed ends. During this process, ARHGEF17 increasingly oligomerizes into clusters that co-localize with myosin filaments, and correlate with their disassembly at lamellas distal edge. ARHGEF17 loss of function leads to decreased RhoA activity at the lamella back and impairs its disassembly. High RhoA activity is however maintained at the lamella front where phosphorylated myosin light chain is observed. We propose that the low contractile, disassembling actomyosin network at the lamella back generates barbed ends leading to ATP-actin production, and ARHGEF17 binding. This then locally activates RhoA-dependent contractility, ensuring robust lamella disassembly through fracturing rather than re-inforcement. ARHGEF17 exemplifies the spatio-temporal complexity of Rho GTPase signaling and the requirement of feedback mechanism for homeostasis of contractile actomyosin networks.