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Published online
doi:10.1083/jcb.200610076
The Journal of Cell Biology, Vol. 177, No. 3, 527-538
The Rockefeller University Press, 0021-9525 $30.00
© Bass et al.
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Article

Syndecan-4–dependent Rac1 regulation determines directional migration in response to the extracellular matrix



Mark D. Bass1, Kirsty A. Roach1, Mark R. Morgan1, Zohreh Mostafavi-Pour1, Tobias Schoen2, Takashi Muramatsu3, Ulrike Mayer1, Christoph Ballestrem1, Joachim P. Spatz2, and Martin J. Humphries1

1 Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK
2 Department of New Materials and Biosystems, Max-Planck-Institute for Metals Research, D-70569 Stuttgart, Germany
3 Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Correspondence to Martin J. Humphries: martin.humphries{at}manchester.ac.uk

Cell migration in wound healing and disease is critically dependent on integration with the extracellular matrix, but the receptors that couple matrix topography to migratory behavior remain obscure. Using nano-engineered fibronectin surfaces and cell-derived matrices, we identify syndecan-4 as a key signaling receptor determining directional migration. In wild-type fibroblasts, syndecan-4 mediates the matrix-induced protein kinase C{alpha} (PKC{alpha})–dependent activation of Rac1 and localizes Rac1 activity and membrane protrusion to the leading edge of the cell, resulting in persistent migration. In contrast, syndecan-4–null fibroblasts migrate randomly as a result of high delocalized Rac1 activity, whereas cells expressing a syndecan-4 cytodomain mutant deficient in PKC{alpha} regulation fail to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix.

Z. Mostafavi-Pour's present address is Dept. of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran.

U. Mayer's present address is School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.

Abbreviations used in this paper: BIM-I, bisindolylmaleimide I; FRET, fluorescence resonance energy transfer; MEF, mouse embryonic fibroblast; PAK, p21-activiated kinase.


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