title: Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix.
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 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.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, England, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bass
authors.forename: Kirsty A
authors.initials: KA
authors.lastname: Roach
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morgan
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Mostafavi-Pour
authors.forename: Tobias
authors.initials: T
authors.lastname: Schoen
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayer
authors.forename: Christoph
authors.initials: C
authors.lastname: Ballestrem
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Spatz
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
mesh_terms: 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
chemical_list: 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