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Abstract
Cortactin is a c-src substrate associated with sites of dynamic actin assembly at
the leading edge of migrating cells. We previously showed that cortactin binds to
Arp2/3 complex, the essential molecular machine for nucleating actin filament assembly.
In this study, we demonstrate that cortactin activates Arp2/3 complex based on direct
visualization of filament networks and pyrene actin assays. Strikingly, cortactin
potently inhibited the debranching of filament networks. When cortactin was added
in combination with the active VCA fragment of N-WASp, they synergistically enhanced
Arp2/3-induced actin filament branching. The N-terminal acidic and F-actin binding
domains of cortactin were both necessary to activate Arp2/3 complex. These results
support a model in which cortactin modulates actin filament dendritic nucleation by
two mechanisms, (1) direct activation of Arp2/3 complex and (2) stabilization of newly
generated filament branch points. By these mechanisms, cortactin may promote the formation
and stabilization of the actin network that drives protrusion at the leading edge
of migrating cells.