Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions

Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions
Nicolas Borghia, Molly Lowndesb, Venkat Maruthamuthuc, Margaret L. Gardelc, and W. James Nelsona,b,d,1
+ Author Affiliations

aDepartment of Biology,
bCancer Biology Program, and
dDepartment of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305; and
cDepartment of Physics, University of Chicago, Chicago, IL 60637

Abstract
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 αE-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.

cell migration cell–cell adhesion alpha-E-catenin micropattern traction forces
Footnotes
1To whom correspondence should be addressed. E-mail: wjnelson@stanford.edu. Author contributions: N.B. and W.J.N. designed research; N.B., M.L., and V.M. performed research; N.B., M.L.G., and W.J.N. contributed new reagents/analytic tools; N.B., M.L., and V.M. analyzed data; and N.B. and W.J.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
See Commentary on page 13199.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1002662107/-/DCSupplemental.

http://www.pnas.org/content/107/30/13324