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Science 327 (5971): 1380-1385

Copyright © 2010 by the American Association for the Advancement of Science

Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

Khalid Salaita,1,2,3,*,{dagger} Pradeep M. Nair,1,2,3,* Rebecca S. Petit,1,2,3 Richard M. Neve,4,{ddagger} Debopriya Das,4 Joe W. Gray,4,5 Jay T. Groves1,2,3,6,§

Abstract: Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

1 Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
2 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3 Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
4 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
5 Department of Laboratory Medicine and Radiation Oncology, University of California, San Francisco, CA 94143, USA.
6 Research Center of Excellence in Mechanobiology, National University of Singapore, Singapore 117543.

* These authors contributed equally to this work.

{dagger} Present address: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.

{ddagger} Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

§ To whom correspondence should be addressed. E-mail: jtgroves{at}

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