Molecular mechanisms of invadopodium formation: The role of the N-WASP-Arp2/3 complex pathway and cofilin

Hideki Yamaguchi, Mike Lorenz, Stephan Kempiak, Corina Sarmiento, Salvatore Coniglio, Marc Symons, Jeffrey Segall, Robert Eddy, Hiroaki Miki, Tadaomi Takenawa, John Condeelis

Research output: Contribution to journalArticle

477 Scopus citations

Abstract

Invadopodia are actin-rich membrane protrusions with a matrix degradation activity formed by invasive cancer cells. We have studied the molecular mechanisms of invadopodium formation in metastatic carcinoma cells. Epidermal growth factor (EGF) receptor kinase inhibitors blocked invadopodium formation in the presence of serum, and EGF stimulation of serum-starved cells induced invadopodium formation. RNA interference and dominant-negative mutant expression analyses revealed that neural WASP (N-WASP), Arp2/3 complex, and their upstream regulators, Nck1, Cdc42, and WIP, are necessary for invadopodium formation. Time-lapse analysis revealed that invadopodia are formed de novo at the cell periphery and their lifetime varies from minutes to several hours. Invadopodia with short lifetimes are motile, whereas long-lived invadopodia tend to be stationary. Interestingly, suppression of cofilin expression by RNA interference inhibited the formation of long-lived invadopodia, resulting in formation of only short-lived invadopodia with less matrix degradation activity. These results indicate that EGF receptor signaling regulates invadopodium formation through the N-WASP-Arp2/3 pathway and cofilin is necessary for the stabilization and maturation of invadopodia.

Original languageEnglish (US)
Pages (from-to)441-452
Number of pages12
JournalJournal of Cell Biology
Volume168
Issue number3
DOIs
StatePublished - Jan 31 2005

ASJC Scopus subject areas

  • Cell Biology

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