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

Abstract

Cortactin, a filamentous actin (F-actin)-associated protein and prominent substrate of Src, is implicated in progression of breast tumours through gene amplification at chromosome 11q13. However, the function of cortactin remains obscure. Here we show that cortactin co-localizes with the Arp2/3 complex, a de novo actin nucleator, at dynamic particulate structures enriched with actin filaments. Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments. The interaction of cortactin with the Arp2/3 complex occurs at an amino-terminal domain that is rich in acidic amino acids. Mutations in a conserved amino-acid sequence of DDW abolish both the interaction with the Arp2/3 complex and complex activation. The N-terminal domain is not only essential but also sufficient to target cortactin to actin-enriched patches within cells. Interestingly, the ability of cortactin to activate the Arp2/3 complex depends on an activity for 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 polymerization involving an enhanced interaction between the Arp2/3 complex and actin filaments.

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Figure 1: Characterization of the interaction of cortactin with the Arp2/3 complex.
Figure 2: Correlation between binding to the Arp2/3 complex and cortactin-mediated stimulation of actin polymerization.
Figure 3: Cortactin stimulates actin polymerization nucleated by the Arp2/3 complex.
Figure 4: Requirement of F-actin binding for cortactin to stimulate the Arp2/3 complex
Figure 5: Requirement of interaction with the Arp2/3 complex for localization of cortactin with actin patches.
Figure 6: Quantification of the co-localization of cortactin variants with the Arp2/3 complex.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, the American Heart Association and the Department of Army.

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Correspondence to Xi Zhan.

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Uruno, T., Liu, J., Zhang, P. et al. Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat Cell Biol 3, 259–266 (2001). https://doi.org/10.1038/35060051

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