From WRC to Arp2/3: Collective molecular mechanisms of branched actin network assembly

Branched actin networks have emerged as major force-generating structures driving the protrusions in various distinct cell types and processes, ranging from lamellipodia operating in mesenchymal and epithelial cell migration or tails pushing intracellular pathogens and vesicles to developing spine heads on neurons. Many key molecular features are conserved among all those Arp2/3 complex-containing, branched actin networks. Here, we will review recent progress in our molec-ular understanding of the core biochemical machinery driving branched actin nucleation, from the generation of filament primers to Arp2/3 activator recruitment, regulation and turn-over. Due to the wealth of information on distinct, Arp2/3 network-containing structures, we are largely focusing-in an exemplary fashion-on canonical lamellipodia of mesen-chymal cells, which are regulated by Rac GTPases, their downstream effector WAVE Regulatory Complex and its target Arp2/3 complex. Novel insight additionally confirms that WAVE and Arp2/3 complexes regulate or are themselves tuned by additional prominent actin regulatory factors, including Ena/ VASP family members and heterodimeric capping protein. Finally, we are considering recent insights into effects exerted by mechanical force, both at the branched network and indi-vidual actin regulator level.