Spatially modulated ephrinA1:EphA2 signaling increases local contractility and global focal adhesion dynamics to promote cell motility

Zhongwen Chen, Dongmyung Oh, Kabir H. Biswas, Cheng Han Yu, Ronen Zaidel-Bar, Jay T. Groves

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)E5696-E5705
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number25
DOIs
StatePublished - Jun 19 2018
Externally publishedYes

Keywords

  • Lipid bilayer
  • Metastasis
  • Microfabrication
  • Single molecule
  • Src

ASJC Scopus subject areas

  • General

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