NHSL3 interacts with Ena/VASP proteins and the Scar/WAVE complex and promotes cell migration.
Tight control of mesenchymal cell migration is important for embryonic development and its deregulation causes disease. It is driven by lamellipodia protrusion, the leading edge of the migrating cell. This is controlled by Rac-Scar/WAVE-Arp2/3 complexes driving actin filament nucleation coupled to Ena/VASP proteins mediating actin filament elongation. These activities are coordinated by leading-edge proteins, such as Lamellipodin and NHSL1. Here, we discovered KIAA1522/NHSL3 as an additional regulator of these essential actin effectors. We reveal that NHSL3 promotes cell migration. NHSL3 co-localises at the edge of lamellipodia with Ena/VASP proteins and the Scar/WAVE complex. We show that it binds to Ena/VASP proteins and the Scar/WAVE complex and functions to inhibit Scar/WAVE-Arp2/3 activity in cells. NHSL3 interacts with the Scar/WAVE complex subunit Abi and, in contrast to other known Scar/WAVE complex binders, additionally to the CYFIP1/2 subunit through 3 short linear motifs. Thus, control of actin filament nucleation and elongation at the leading edge of mesenchymal cells is more complex than anticipated. Our study provides insights into the intricate regulation of lamellipodial actin networks highly relevant for understanding control of mesenchymal cell migration during development and diseases.