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Published online 21 April 2003. doi:10.1083/jcb.200209057
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© The Rockefeller University Press, 0021-9525/2003/4/371 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 371-380

Article

 Pointed-end capping by tropomodulin3 negatively regulates endothelial cell motility

Robert S. Fischer, Kimberly L. Fritz-Six and Velia M. Fowler

Department of Cell Biology, The Scripps Research Instititute, La Jolla, CA 92037

Address correspondence to Velia M. Fowler, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB163, La Jolla, CA 92037. Tel.: (858) 784-8277. Fax: (858) 784-8753. E-mail: velia{at}scripps.edu

Actin filament pointed-end dynamics are thought to play a critical role in cell motility, yet regulation of this process remains poorly understood. We describe here a previously uncharacterized tropomodulin (Tmod) isoform, Tmod3, which is widely expressed in human tissues and is present in human microvascular endothelial cells (HMEC-1). Tmod3 is present in sufficient quantity to cap pointed ends of actin filaments, localizes to actin filament structures in HMEC-1 cells, and appears enriched in leading edge ruffles and lamellipodia. Transient overexpression of GFP–Tmod3 leads to a depolarized cell morphology and decreased cell motility. A fivefold increase in Tmod3 results in an equivalent decrease in free pointed ends in the cells. Unexpectedly, a decrease in the relative amounts of F-actin, free barbed ends, and actin-related protein 2/3 (Arp2/3) complex in lamellipodia are also observed. Conversely, decreased expression of Tmod3 by RNA interference leads to faster average cell migration, along with increases in free pointed and barbed ends in lamellipodial actin filaments. These data collectively demonstrate that capping of actin filament pointed ends by Tmod3 inhibits cell migration and reveal a novel control mechanism for regulation of actin filaments in lamellipodia.

Key Words: cytoskeleton; angiogenesis; actin; tropomyosin; lamellipodia

The online version of this article includes supplemental material.

* Abbreviations used in this paper: Ad, adenovirus; ADF, actin-depolymerizing factor; Arp2/3, actin-related protein 2/3; CB, cytoskeleton buffer; DBP, vitamin D–binding protein; HMEC-1, human microvascular endothelial cells; siRNA, small interfering RNA; TM, tropomyosin; Tmod, tropomodulin; tTA, tet transcriptional activator.


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