Syndecan-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 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 Calpha (PKCalpha)-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 PKCalpha regulation fail to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix.
Bass
Mark D
MD
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, England, UK.
Roach
Kirsty A
KA
Morgan
Mark R
MR
Mostafavi-Pour
Zohreh
Z
Schoen
Tobias
T
Muramatsu
Takashi
T
Mayer
Ulrike
U
Ballestrem
Christoph
C
Spatz
Joachim P
JP
Humphries
Martin J
MJ
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D005109:Extracellular Matrix; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000172:deficiency / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D005353:Fibronectins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D051571:Protein Kinase C-alpha; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein