@article{d49384d5dc6241c7a32ccf5a1de8d235,
title = "Spatially modulated ephrinA1:EphA2 signaling increases local contractility and global focal adhesion dynamics to promote cell motility",
abstract = "Recent studies have revealed pronounced effects of the spatial distribution of EphA2 receptors on cellular response to receptor activation. However, little is known about molecular mechanisms underlying this spatial sensitivity, in part due to lack of experimental systems. Here, we introduce a hybrid live-cell patterned supported lipid bilayer experimental platform in which the sites of EphA2 activation and integrin adhesion are spatially controlled. Using a series of live-cell imaging and single-molecule tracking experiments, we map the transmission of signals from ephrinA1:EphA2 complexes. Results show that ligand-dependent EphA2 activation induces localized myosin-dependent contractions while simultaneously increasing focal adhesion dynamics throughout the cell. Mechanistically, Src kinase is activated at sites of ephrinA1:EphA2 clustering and subsequently diffuses on the membrane to focal adhesions, where it up-regulates FAK and paxillin tyrosine phosphorylation. EphrinA1:EphA2 signaling triggers multiple cellular responses with differing spatial dependencies to enable a directed migratory response to spatially resolved contact with ephrinA1 ligands.",
keywords = "Lipid bilayer, Metastasis, Microfabrication, Single molecule, Src",
author = "Zhongwen Chen and Dongmyung Oh and Biswas, {Kabir H.} and Yu, {Cheng Han} and Ronen Zaidel-Bar and Groves, {Jay T.}",
note = "Funding Information: We thank Dr. Bai Funing and Ms. Ong Huiting for their help with Matlab programming. We also thank Dr. Adrienne Greene (J.T.G. laboratory, University of California, Berkeley) for her contribution of purified ephrinA1 protein, as well as helpful discussions. We thank Dr. Kevin Hartman's help in the beginning of this project. We thank other members in J.T.G. laboratory, R.Z.-B. laboratory, and Michael Sheetz laboratory for stimulating discussions and sharing of reagents. This work was supported by National Institutes of Health National Cancer Institute Physical Sciences in Oncology Network Project 1-U01CA202241. Collaborative work at the Mechanobiology Institute, National University of Singapore, was supported by CRP001-084. Funding Information: ACKNOWLEDGMENTS. We thank Dr. Bai Funing and Ms. Ong Huiting for their help with Matlab programming. We also thank Dr. Adrienne Greene (J.T.G. laboratory, University of California, Berkeley) for her contribution of purified ephrinA1 protein, as well as helpful discussions. We thank Dr. Kevin Hartman{\textquoteright}s help in the beginning of this project. We thank other members in J.T.G. laboratory, R.Z.-B. laboratory, and Michael Sheetz laboratory for stimulating discussions and sharing of reagents. This work was supported by National Institutes of Health National Cancer Institute Physical Sciences in Oncology Network Project 1-U01CA202241. Collaborative work at the Mechanobiology Institute, National University of Singapore, was supported by CRP001-084. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
month = jun,
day = "19",
doi = "10.1073/pnas.1719961115",
language = "English (US)",
volume = "115",
pages = "E5696--E5705",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "25",
}