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Vol. 20, Issue 3, 948-962, February 1, 2009

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Supervillin Reorganizes the Actin Cytoskeleton and Increases Invadopodial Efficiency

Department of Cell Biology and Cell Dynamics Program, University of Massachusetts Medical School, Worcester, MA 01605

Submitted August 22, 2008; Revised November 26, 2008; Accepted December 4, 2008
Monitoring Editor: Joan Brugge

Tumor cells use actin-rich protrusions called invadopodia to degrade extracellular matrix (ECM) and invade tissues; related structures, termed podosomes, are sites of dynamic ECM interaction. We show here that supervillin (SV), a peripheral membrane protein that binds F-actin and myosin II, reorganizes the actin cytoskeleton and potentiates invadopodial function. Overexpressed SV induces redistribution of lamellipodial cortactin and lamellipodin/RAPH1/PREL1 away from the cell periphery to internal sites and concomitantly increases the numbers of F-actin punctae. Most punctae are highly dynamic and colocalize with the podosome/invadopodial proteins, cortactin, Tks5, and cdc42. Cortactin binds SV sequences in vitro and contributes to the formation of enhanced green fluorescent protein (EGFP)-SV induced punctae. SV localizes to the cores of Src-generated podosomes in COS-7 cells and with invadopodia in MDA-MB-231 cells. EGFP-SV overexpression increases average numbers of ECM holes per cell; RNA interference-mediated knockdown of SV decreases these numbers. Although SV knockdown alone has no effect, simultaneous down-regulation of SV and the closely related protein gelsolin reduces invasion through ECM. Together, our results show that SV is a component of podosomes and invadopodia and that SV plays a role in invadopodial function, perhaps as a mediator of cortactin localization, activation state, and/or dynamics of metalloproteinases at the ventral cell surface.

Address correspondence to: Elizabeth J. Luna (elizabeth.luna{at}umassmed.edu)

Abbreviations used: ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; MMP, matrix metalloproteinase; pTyr, phosphotyrosine; SmAV, smooth muscle isoform of supervillin; SV, supervillin.

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