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Vol. 15, Issue 10, 4682-4694, October 2004

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A Critical Role of Tropomyosins in TGF- Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

Andrei V. Bakin ^* , Alfiya Safina ^*, Cammie Rinehart , Cecilia Daroqui , Huferesh Darbary ^*, and David M. Helfman ^|| ¶

^* Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263; Department of Medicine, Vanderbilt University, Nashville, TN 37232; Research Area, Institute of Oncology "Angel H. Roffo," Buenos Aires, Argentina, C1417DTB; and ^|| Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724

Submitted April 29, 2004; Revised July 8, 2004; Accepted August 4, 2004
Monitoring Editor: Thomas Pollard

We have investigated transforming growth factor beta (TGF-)–mediated induction of actin stress fibers in normal and metastatic epithelial cells. We found that stress fiber formation requires de novo protein synthesis, p38Mapk and Smad signaling. We show that TGF- via Smad and p38Mapk up-regulates expression of actin-binding proteins including high-molecular-weight tropomyosins, -actinin and calponin h2. We demonstrate that, among these proteins, tropomyosins are both necessary and sufficient for TGF- induction of stress fibers. Silencing of tropomyosins with short interfering RNAs (siRNAs) blocks stress fiber assembly, whereas ectopic expression of tropomyosins results in stress fibers. Ectopic-expression and siRNA experiments show that Smads mediate induction of tropomyosins and stress fibers. Interestingly, TGF- induction of stress fibers was not accompanied by changes in the levels of cofilin phosphorylation. TGF- induction of tropomyosins and stress fibers are significantly inhibited by Ras-ERK signaling in metastatic breast cancer cells. Inhibition of the Ras-ERK pathway restores TGF- induction of tropomyosins and stress fibers and thereby reduces cell motility. These results suggest that induction of tropomyosins and stress fibers play an essential role in TGF- control of cell motility, and the loss of this TGF- response is a critical step in the acquisition of metastatic phenotype by tumor cells.

Abbreviations used: TGF-, transforming growth factor beta; Mapk, mitogene-activated protein kinase; TM, tropomyosin; siRNA, short-interfering RNA. NMuMG cells that were untreated or treated with 2 ng/ml TGF-1 for 24 h in the absence or presence of 10 µM SB202190. The data represent an average of three independent experiments. Actn1, -actinin1, Tpm3, tropomyosin3; Tpm4, tropomysin4; Cnn2 (H2), calponin2 (H2).

^¶ Present address: Department of Cell Biology and Anatomy, University of Miami School of Medicine, P.O. Box 019136, Miami, FL 33136.

Corresponding author. E-mail address: andrei.bakin{at}roswellpark.org.

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