Identification of an Actin Binding Region and a Protein Kinase C Phosphorylation Site on Human Fascin

Ono, Shoichiro; Yamakita, Yoshihiko; Yamashiro, Shigeko; Matsudaira, Paul; Gnarra, James R.; Obinata, Takashi; Matsumura, Fumio

doi:10.1074/jbc.272.4.2527

Cited by 171 publications

(197 citation statements)

References 39 publications

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“…Fascin immunoreactivity may thus be considered a more reliable tool for better assessing the biological aggressiveness and clinical course of NSCLC. Furthermore, the inhibition of fascin activity by phosphorylation (Yamakita et al, 1996, Ono et al, 1997, Tilney et al, 1998Adams et al, 1999, Cohan et al, 2001 or antisense oligonucleotide strategy (Al-Alwan et al, 2001) could represent potentially novel therapeutic options in the treatment of lung cancer. The validation of differentially expressed fascin levels in NSCLC could open new diagnostic and therapeutic perspectives, such as the development of radiologic imaging systems based on tagged antibody strategy to detect small lung cancers, either primary or metastatic, or the strategy of cell-mediated or antibody-based immunotherapy using fascin for targeting more aggressive lung carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer

et al. 2003

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Fascin-1, the most expressed form of fascin in vertebrate tissues, is an actin-bundling protein that induces cell membrane protrusions and increases motility of normal and transformed epithelial cells. Very few data are available on the role of this protein in nonsmall cell lung cancer (NSCLC). Two hundred and twenty patients with stage I NSCLC and long-term follow-up were evaluated immunocytochemically for fascin expression. Overall, variable fascin immunoreactivity was detected in 98% of 116 squamous cell carcinomas, in 78% of 96 adenocarcinomas, in 83% of six large cell carcinomas, and in the two adenosquamous carcinomas under study. Neoplastic emboli were commonly decorated by the antifascin antibody (Po0.001), also when the surrounding invasive carcinoma was unreactive. Fascin immunoreactivity correlated with high tumour grade (P ¼ 0.017) and, in adenocarcinomas, with high Ki-67 labelling index (P ¼ 0.021). Adenocarcinomas with a prevalent bronchiolo-alveolar in situ component were less commonly immunoreactive for fascin than invasive tumours (P ¼ 0.005). Contralateral thoracic or distant metastases were associated significantly with diffuse (460% immunoreactive tumour cells) fascin expression in adenocarcinomas (P ¼ 0.043), and marginally with strong fascin immunostaining in squamous cell carcinomas (P ¼ 0.13). No associations were noted with any other clinicopathological variables tested. Patients with tumours showing diffuse (460% immunoreactive neoplastic cells) and/or strong immunoreactivity for fascin had a shorter survival (P ¼ 0.006 for adenocarcinomas and P ¼ 0.026 for squamous cell carcinomas), even after multivariate analysis (P ¼ 0.014 and 0.050, respectively). The current study documents for the first time that fascin is upregulated in invasive and more aggressive NSCLC, being an independent prognostic predictor of unfavourable clinical course of the disease. Targetting the fascin pathway could be a novel therapeutic strategy of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer

et al. 2003

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“…In either case, the net result would be improper cross-linking by fascin. Interestingly, work from Matsumura's laboratory has shown that whereas phosphorylation by kinases can regulate actin–fascin interactions in vitro (Yamakita et al 1996; Shoichiro et al 1997), the stoichiometry of in vivo phosphorylation is low, suggesting that other mechanisms control fascin–actin interactions under normal conditions. In addition, since only tiny bundles form during staurosporine treatment as assayed either by our phalloidin staining or our thin sections, the forked cross-link may also be affected either directly or indirectly by this drug.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Actin Filament Cross-linking and Bundle Shape in Drosophila Bristles

Tilney

Connelly

Vranich

et al. 2000

The Journal of Cell Biology

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Previous studies demonstrate that in developing Drosophila bristles, two cross-linking proteins are required sequentially to bundle the actin filaments that support elongating bristle cells. The forked protein initiates the process and facilitates subsequent cross-linking by fascin. Using cross-linker–specific antibodies, mutants, and drugs we show that fascin and actin are present in excessive amounts throughout bundle elongation. In contrast, the forked cross-linker is limited throughout bundle formation, and accordingly, regulates bundle size and shape. We also show that regulation of cross-linking by phosphorylation can affect bundle size. Specifically, inhibition of phosphorylation by staurosporine results in a failure to form large bundles if added during bundle formation, and leads to a loss of cross-linking by fascin if added after the bundles form. Interestingly, inhibition of dephosphorylation by okadaic acid results in the separation of the actin bundles from the plasma membrane. We further show by thin section electron microscopy analysis of mutant and wild-type bristles that the amount of material that connects the actin bundles to the plasma membrane is also limited throughout bristle elongation. Therefore, overall bundle shape is determined by the number of actin filaments assembled onto the limited area provided by the connector material. We conclude that assembly of actin bundles in Drosophila bristles is controlled in part by the controlled availability of a single cross-linking protein, forked, and in part by controlled phosphorylation of cross-links and membrane actin connector proteins.

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“…PKC-mediated phosphorylation at serine 39 reduces the actin-bundling activity of fascin, resulting in its disappearance from actin microspikes (Yamakita et al, 1996;Ono et al, 1997). Because PKC activity is influenced to some extent by the rho family GTPases, as a result of their effects on phosphatidylinositol 4,5-bisphosphate metabolism (Stossel, 1993;Chong et al, 1994;Hartwig et al, 1995), engagement of NG2 may alter the level of fascin phosphorylation, resulting in changes in the dynamics of the actinfascin association.…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Fang

Burg

Barritt

et al. 1999

MBoC

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Cells expressing the NG2 proteoglycan can attach, spread, and migrate on surfaces coated with NG2 mAbs, demonstrating that engagement of NG2 can trigger the cytoskeletal rearrangements necessary for changes in cell morphology and motility. Engagement of different epitopes of the proteoglycan results in distinct forms of actin reorganization. On mAb D120, the cells contain radial actin spikes characteristic of filopodial extension, whereas on mAb N143, the cells contain cortical actin bundles characteristic of lamellipodia. Cells that express NG2 variants lacking the transmembrane and cytoplasmic domains are unable to spread or migrate on NG2 mAb-coated surfaces, indicating that these portions of the molecule are essential for NG2-mediated signal transduction. Cells expressing an NG2 variant lacking the C-terminal half of the cytoplasmic domain can still spread normally on mAbs D120 and N143, suggesting that the membraneproximal cytoplasmic segment is responsible for this process. In contrast, this variant migrates poorly on mAb D120 and exhibits abnormal arrays of radial actin filaments decorated with fascin during spreading on this mAb. The C-terminal portion of the NG2 cytoplasmic domain, therefore, may be involved in regulating molecular events that are crucial for cell motility.

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Identification of an Actin Binding Region and a Protein Kinase C Phosphorylation Site on Human Fascin

Cited by 171 publications

References 39 publications

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer

Regulation of Actin Filament Cross-linking and Bundle Shape in Drosophila Bristles

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

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