Activation of Arp2/3 complex-mediated actin polymerization by cortactin

Cortactin, a filamentous actin (F-actin)-associated protein and prominent s ubstrate of Src, is implicated in progression of breast tumours through gen e amplification at chromosome 11q13. However, the function of cortactin rem ains obscure. Here we show that cortactin co-localizes with the Arp2/3 comp lex, a de novo actin nucleator, at dynamic particulate structures enriched with actin filaments. Cortactin binds directly to the Arp2/3 complex and ac tivates it to promote nucleation of actin filaments. The interaction of cor tactin with the Arp2/3 complex occurs at an amino-terminal domain that is r ich in acidic amino acids. Mutations in a conserved amino-acid sequence of DDW abolish both the interaction with the Arp2/3 complex and complex activa tion. The N-terminal domain is not only essential but also sufficient to ta rget cortactin to actin-enriched patches within cells. Interestingly, the a bility of cortactin to activate the Arp2/3 complex depends on an activity f or F-actin binding; which is almost 20-fold higher than that of the Arp2/3 complex. Our data indicate a new mechanism for activation of actin polymeri zation involving an enhanced interaction between the Arp2/3 complex and act in filaments.