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First published online August 20, 2008
doi: 10.1242/10.1242/jcs.022509

Journal of Cell Science 121, 2805-2813 (2008)
Published by The Company of Biologists 2008
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Research Article

Rac regulates the interaction of fascin with protein kinase C in cell migration

Maddy Parsons1,* and Josephine C. Adams2,3,*

1 Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL, UK
2 Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
3 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

* Authors for correspondence (e-mail: adamsj{at}ccf.org; maddy.parsons{at}kcl.ac.uk)

Accepted 13 May 2008

Fascin is an actin-bundling protein that is low or absent in normal epithelia; its upregulation correlates with poor prognosis in many human carcinomas. We have recently demonstrated in mouse xenograft models that fascin contributes to tumour development and metastasis through its dual actin-bundling and active PKC-binding activities. Rac was implicated as a regulator of fascin-dependent colon carcinoma cell migration in vitro. Here, we tested the hypothesis that Rac regulates the interaction of fascin with active PKC. The major conventional PKC in colon carcinoma cells is protein kinase C{gamma} (PKC{gamma}). Endogenous PKC{gamma}, fascin and Rac1 colocalised at lamellipodial margins of migrating cells. Colocalisation of fascin and PKC{gamma} depended on Rac activity, and inhibition of Rac decreased PKC{gamma} activity in cell extracts but not in vitro. Fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy uncovered that fascin and PKC{gamma} interact in protrusions and filopodia of migrating cells. Mechanistically, the interaction depended on phosphorylated fascin, active PKC{gamma} and active Rac, but not on active Cdc42. The activity of Rac on the fascin/PKC complex was mediated in part by Pak. Elucidation of this novel pathway for regulation of the fascin/PKC{gamma} complex in migrating carcinoma cells suggests novel targets for therapeutic intervention in metastasis.

Key words: Cell protrusions, Filopodia, Migration, Signalling, Rac, Pak


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