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Vol. 16, Issue 8, 3678-3691, August 2005

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Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

Ritu Chakravarti ^*, Vasileia Sapountzi  , and Josephine C. Adams ^* 

^* Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; MRC Laboratory for Molecular Cell Biology and Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom

Submitted October 19, 2004; Revised May 11, 2005; Accepted May 25, 2005
Monitoring Editor: Mark Ginsberg

Cell protrusions contribute to cell motility and migration by mediating the outward extension and initial adhesion of cell edges. In many cells, these extensions are supported by actin bundles assembled by the actin cross-linking protein, fascin. Multiple extracellular cues regulate fascin and here we focus on the mechanism by which the transmembrane proteoglycan, syndecan-1, specifically activates lamellipodial cell spreading and fascin-and-actin bundling when clustered either by thrombospondin-1, laminin, or antibody to the syndecan-1 extracellular domain. There is almost no knowledge of the signaling mechanisms of syndecan-1 cytoplasmic domain and we have tested the hypothesis that the unique V region of syndecan-1 cytoplasmic domain has a crucial role in these processes. By four criteria—the activities of N-cadherin/V region chimeras, syndecan-1 deletion mutants, or syndecan-1 point mutants, and specific inhibition by a membrane-permeable TAT-V peptide—we demonstrate that the V region is necessary and sufficient for these cell behaviors and map the molecular basis for its activity to multiple residues located across the V region. These activities correlate with a V-region-dependent incorporation of cell-surface syndecan-1 into a detergent-insoluble form. We also demonstrate functional roles of syndecan-1 V region in laminin-dependent C2C12 cell adhesion and three-dimensional cell migration. These data identify for the first time specific cell behaviors that depend on signaling through the V region of syndecan-1.

Abbreviations used: ECM, extracellular matrix; EGFP, enhanced green fluorescent protein; GAG, glycosaminoglycan; JP, jasplakinolide; MbCD, 6-monodeoxy-6-monoamino-b-cyclodextrin; NCAD, N-cadherin; TSP-1, thrombospondin-1; VBS, vinblastine sulphate.

Present address: Prostate Research Group, Northern Institute for Cancer Research, University of Newcastle Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.

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

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