Cytoskeleton remodelling by cooperating small GTPases at the membrane
Dr. Daniel Humphreys, University of Cambridge
Rho small GTPases are master regulators of cell function and they control actin filament polymerisation from the membrane where they are anchored by acylation. The Rho GTPase Rac1 is known to mediate actin polymerisation through the WAVE regulatory complex (WRC) which is pivotal to cell motility and macropinocytosis. The membrane is critical to Rac1 function but studying small GTPase signalling at the membrane is challenging and often neglected. Our group has addressed this challenge by developing microspheres coated in defined phospholipid bilayers that enable the reconstitution of signalling pathways at the membrane in cell-free extract. To our surprise, membrane-anchored Rac1 was found to be insufficient for WRC activation. Instead, WRC activity required an unexpected collaboration between Rac1 and Arf GTPase, revealing a novel crosstalk between small GTPase families. Unravelling WRC regulation continues to resolve how cytoskeletal networks are controlled and how bacterial pathogens subvert small GTPase crosstalk to establish human infections.