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Dual actin-bundling and protein kinase C-binding activities of fascin regulate carcinoma cell migration downstream of Rac and contribute to metastasis.

ABSTRACT: 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.

SUBMITTER: Hashimoto Y

PROVIDER: S-EPMC2043557 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Dual actin-bundling and protein kinase C-binding activities of fascin regulate carcinoma cell migration downstream of Rac and contribute to metastasis.

Hashimoto Yosuke Y Parsons Maddy M Adams Josephine C JC

Molecular biology of the cell 20070912 11

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 aggress ...[more]

PMID: 17855511

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Project description:The assembly of actin-based structures with precisely defined architectures supports essential cellular functions, including motility, intracellular transport, and division. The geometric arrangements of the filaments within actin structures are stabilized via the association of crosslinking proteins, which bind two filaments simultaneously. Because actin polymerization and crosslinking occur concurrently within the dynamic environment of the cell, these processes likely play interdependent roles in shaping the architectures of actin-based structures. To dissect the contribution of polymerization to the construction of higher-order actin structures, we investigated how filament elongation affects the formation of simple, polarized actin bundles by the crosslinking protein fascin. Using populations of actin filaments to represent distinct stages of elongation, we found that the rate of bundle assembly increases with filament length. Fascin assembles short filaments into discrete bundles, whereas bundles of long filaments merge with one another to form interconnected networks. Although filament elongation promotes bundle coalescence, many connections formed between elongating bundles are short-lived and are followed by filament breakage. Our data suggest that initiation of crosslinking early in elongation aligns growing filaments, creating a template for continued bundle assembly as elongation proceeds. This initial alignment promotes the assembly of bundles that are resistant to large changes in curvature that are required for coalescence into interconnected networks. As a result, bundles of short filaments remain straighter and more topologically discrete as elongation proceeds than bundles assembled from long filaments. Thus, uncoordinated filament elongation and crosslinking can alter the architecture of bundled actin networks, highlighting the importance of maintaining precise control over filament length during the assembly of specialized actin structures.

Dataset Information

Dual actin-bundling and protein kinase C-binding activities of fascin regulate carcinoma cell migration downstream of Rac and contribute to metastasis.

Publications

Dual actin-bundling and protein kinase C-binding activities of fascin regulate carcinoma cell migration downstream of Rac and contribute to metastasis.

Similar Datasets

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