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

Author:

Bass Mark D.1,Roach Kirsty A.1,Morgan Mark R.1,Mostafavi-Pour Zohreh1,Schoen Tobias2,Muramatsu Takashi3,Mayer Ulrike1,Ballestrem Christoph1,Spatz Joachim P.2,Humphries Martin J.1

Affiliation:

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

Abstract

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 Cα (PKCα)–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 PKCα regulation fail to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix.

Publisher

Rockefeller University Press

Subject

Cell Biology

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