The power of epithelia to migrate and cover wounds is essential to maintaining their functions as physical barriers. epithelial cells. Here we examine the hypothesis that edges which are universally and continuously present in wounds are a cue. Using a novel culture model we find that their existence is enough to trigger activation from the EGFR and elevated motility of cells in the lack of various other cues. Sides that are bordered by agarose usually do not induce activation from the EGFR indicating that activation is not due to loss of any specific type of cell-cell conversation but rather due to loss of physical constraints. INTRODUCTION Wound healing in the skin and cornea is the result of complex and carefully orchestrated processes that include inflammation cell migration and division SGI 1027 and extracellular matrix production and remodeling (Fini and Stramer 2005 ; Gurtner (2003) in this system. Activation of EGFR-ERK1/2 Signaling Requires the Presence of Unconstrained Edges To establish whether the lack of physical constraints is usually a prerequisite for activation of the EGFR-ERK1/2 pathway we seeded HCLE cells on plastic-covered polyHEMA-coated tissue culture plates that were sprayed with agarose droplets (Block (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-12-1026) SGI 1027 on May 12 2010 Recommendations Abercrombie M. Contact inhibition and malignancy. Nature. 1979;281:259-262. [PubMed]Bindschadler M. McGrath J. L. Sheet migration by wounded monolayers as an emergent property of single-cell dynamics. J. Cell Sci. 2007;120:876-884. [PubMed]Bjorklund M. Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim. Biophys. Acta. 2005;1755:37-69. [PubMed]Block E. R. Klarlund J. K. Wounding CAB39L linens of epithelial cells activates the epidermal growth factor receptor through distinct short- and long-range mechanisms. Mol. Biol. Cell. 2008;19:4909-4917. [PMC free article] [PubMed]Block E. R. Matela A. R. SundarRaj N. Iszkula E. R. Klarlund J. K. Wounding induces motility in linens of corneal epithelial cells through loss of spatial constraints: role of heparin-binding epidermal growth factor-like growth factor signaling. J. Biol. Chem. 2004;279:24307-24312. [PubMed]Boucher I. Yang L. Mayo C. Klepeis V. Trinkaus-Randall V. Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway. Exp. Vision Res. 2007;85:130-141. [PMC free article] [PubMed]Brem H. Stojadinovic O. Diegelmann R. F. Entero H. Lee B. Pastar I. Golinko M. Rosenberg H. Tomic-Canic M. Molecular markers in patients with chronic wounds to guide surgical debridement. Mol. Med. 2007;13:30-39. [PMC free article] [PubMed]Brown D. SGI 1027 C. Gatter K. C. Ki67 protein: the immaculate deception? Histopathology. 2002;40:2-11. [PubMed]Cabodi S. Moro L. Bergatto E. Boeri Erba E. Di Stefano P. Turco E. Tarone G. Defilippi P. Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses. Biochem. Soc. Trans. 2004;32:438-442. [PubMed]Cai Y. Sheetz M. P. Pressure propagation across cells: mechanical coherence of dynamic cytoskeletons. Curr. Opin. Cell Biol. 2009;21:47-50. [PubMed]Carmona-Fontaine C. Matthews H. K. Kuriyama S. Moreno SGI 1027 M. Dunn G. A. Parsons M. Stern C. D. Mayor R. Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature. 2008;456:957-961. [PMC free article] [PubMed]Cereijido M. Robbins E. S. Dolan W. J. Rotunno C. A. Sabatini SGI 1027 D. D. Polarized monolayers formed by epithelial cells on a permeable and translucent support. J. Cell Biol. 1978;77:853-880. [PMC free article] [PubMed]Chen C. S. Mechanotransduction-a field pulling together? J. Cell Sci. 2008;121:3285-3292. [PubMed]Cortes-Reynosa P. Robledo T. Macias-Silva M. Wu S. V. Salazar E. P. Src kinase regulates metalloproteinase-9 secretion induced by type IV collagen in MCF-7 human breast malignancy cells. Matrix Biol. 2008;27:220-231. [PubMed]del Rio A. Perez-Jimenez R. Liu R. Roca-Cusachs P. Fernandez J. M. Sheetz M. P. Stretching single talin rod molecules activates vinculin binding. Science. 2009;323:638-641. [PubMed]DeMali K. A. Burridge K. Coupling membrane protrusion and cell adhesion. J. Cell Sci. 2003;116:2389-2397..