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Published online
doi:10.1083/jcb.200812176
The Journal of Cell Biology, Vol. 186, No. 4, 571-587
The Rockefeller University Press, 0021-9525 $30.00
© Oser et al.
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Article

Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation



Matthew Oser1, Hideki Yamaguchi3,4, Christopher C. Mader5,6, J.J. Bravo-Cordero1,2, Marianela Arias1, Xiaoming Chen1, Vera DesMarais1, Jacco van Rheenen1,2,7, Anthony J. Koleske6, and John Condeelis1,2

1 Department of Anatomy and Structural Biology and 2 Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461
3 Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
4 PRESTO, JST, Saitama 332-0012, Japan
5 Department of Cell Biology and 6 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
7 Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584, Netherlands

Correspondence to Matthew Oser: moser{at}aecom.yu.edu

Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. The mechanisms regulating invadopodium assembly and maturation are not understood. We have dissected the stages of invadopodium assembly and maturation and show that invadopodia use cortactin phosphorylation as a master switch during these processes. In particular, cortactin phosphorylation was found to regulate cofilin and Arp2/3 complex–dependent actin polymerization. Cortactin directly binds cofilin and inhibits its severing activity. Cortactin phosphorylation is required to release this inhibition so cofilin can sever actin filaments to create barbed ends at invadopodia to support Arp2/3-dependent actin polymerization. After barbed end formation, cortactin is dephosphorylated, which blocks cofilin severing activity thereby stabilizing invadopodia. These findings identify novel mechanisms for actin polymerization in the invadopodia of metastatic carcinoma cells and define four distinct stages of invadopodium assembly and maturation consisting of invadopodium precursor formation, actin polymerization, stabilization, and matrix degradation.

Abbreviations used in this paper: FN, fibronectin; IP, immunoprecipitation; KD, knockdown; mgv, mean gray value; MMP, matrix metalloproteinase; NTA domain, N-terminal acidic domain; WT, wild type.

© 2009 Oser et al.
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