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

Cell migration in wound healing and disease is critically dependent on integration with the extra-cellular 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 fall to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix.