Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions.
During normal development and in disease, cohesive tissues undergo rearrangements that require integration of signals from cell adhesions to neighboring cells and to the extracellular matrix (ECM). How a range of cell behaviors is coordinated by these different adhesion complexes is unknown. To analyze epithelial cell motile behavior in response to combinations of cell-ECM and cell-cell adhesion cues, we took a reductionist approach at the single-cell scale by using unique, functionalized micropatterned surfaces comprising alternating stripes of ECM (collagenIV) and adjustable amounts of E-cadherin-Fc (EcadFc). On these surfaces, individual cells spatially segregated integrin- and cadherin-based complexes between collagenIV and EcadFc surfaces, respectively. Cell migration required collagenIV and did not occur on surfaces functionalized with only EcadFc. However, E-cadherin adhesion dampened lamellipodia activity on both collagenIV and EcadFc surfaces and biased the direction of cell migration without affecting the migration rate, all in an EcadFc concentration-dependent manner. Traction force microscopy showed that spatial confinement of integrin-based adhesions to collagenIV stripes induced anisotropic cell traction on collagenIV and migration directional bias. Selective depletion of different pools of alphaE-catenin, an E-cadherin and actin binding protein, identified a membrane-associated pool required for E-cadherin-mediated adhesion and down-regulation of lamellipodia activity and a cytosolic pool that down-regulated the migration rate in an E-cadherin adhesion-independent manner. These results demonstrate that there is crosstalk between E-cadherin- and integrin-based adhesion complexes and that E-cadherin regulates lamellipodia activity and cell migration directionality, but not cell migration rate.
Borghi
Nicolas
N
Department of Biology, Cancer Biology Program, Stanford University, Stanford, CA 94305, USA.
Lowndes
Molly
M
Maruthamuthu
Venkat
V
Gardel
Margaret L
ML
Nelson
W James
WJ
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D024141:Collagen Type IV / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D016023:Integrins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D011554:Pseudopodia / Q000502:physiology; D034622:RNA Interference; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000502:physiology*; D016596:Vinculin / Q000235:genetics / Q000378:metabolism; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D024141:Collagen Type IV; D007141:Immunoglobulin Fc Fragments; D016023:Integrins; D051178:alpha Catenin; D016596:Vinculin; D049452:Green Fluorescent Proteins