QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 11, 4591-4602, November 2007

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E07-02-0157v1 18/11/4591    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hashimoto, Y. Articles by Adams, J. C. Search for Related Content PubMed PubMed Citation Articles by Hashimoto, Y. Articles by Adams, J. C.

Dual Actin-bundling and Protein Kinase C-binding Activities of Fascin Regulate Carcinoma Cell Migration Downstream of Rac and Contribute to Metastasis

Yosuke Hashimoto^*, Maddy Parsons, and Josephine C. Adams^*,

*Department of Cell Biology, Lerner Research Institute, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, The Cleveland Clinic, Cleveland, OH 44195; and Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL, United Kingdom

Submitted February 21, 2007; Revised August 29, 2007; Accepted August 31, 2007
Monitoring Editor: Yu-li Wang

Recurrence of carcinomas due to cells that migrate away from the primary tumor is a major problem in cancer treatment. Immunohistochemical analyses of human carcinomas have consistently correlated up-regulation of the actin-bundling protein fascin with a clinically aggressive phenotype and poor prognosis. To understand the functional and mechanistic contributions of fascin, we undertook inducible short hairpin RNA (shRNA) knockdown of fascin in human colon carcinoma cells derived from an aggressive primary tumor. Fascin-depletion led to decreased numbers of filopodia and altered morphology of cell protrusions, decreased Rac-dependent migration on laminin, decreased turnover of focal adhesions, and, in vivo, decreased xenograft tumor development and metastasis. cDNA rescue of fascin shRNA-knockdown cells with wild-type green fluorescent protein-fascin or fascins mutated at the protein kinase C (PKC) phosphorylation site revealed that both the actin-bundling and active PKC-binding activities of fascin are required for the organization of filopodial protrusions, Rac-dependent migration, and tumor metastasis. Thus, fascin contributes to carcinoma migration and metastasis through dual pathways that impact on multiple subcellular structures needed for cell migration.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Josephine C. Adams (adamsj{at}ccf.org)

Abbreviations used: BIM, bisindolylmaleimide I; IKD, inducible knockdown; LN, laminin; mRFP, monomer red fluorescent protein; shRNA, short hairpin RNA; TetR, tetracycline repressor.

This article has been cited by other articles:

				A. D. Darnel, E. Behmoaram, R. T. Vollmer, J. Corcos, K. Bijian, K. Sircar, J. Su, J. Jiao, M. A. Alaoui-Jamali, and T. A. Bismar Fascin Regulates Prostate Cancer Cell Invasion and Is Associated with Metastasis and Biochemical Failure in Prostate Cancer Clin. Cancer Res., February 15, 2009; 15(4): 1376 - 1383. [Abstract] [Full Text] [PDF]

				M. Parsons and J. C. Adams Rac regulates the interaction of fascin with protein kinase C in cell migration J. Cell Sci., September 1, 2008; 121(17): 2805 - 2813. [Abstract] [Full Text] [PDF]