Abstract
Interactions between receptor tyrosine kinases of the Eph family and their ligands, ephrins, are implicated in establishment of organ boundaries and repulsive guidance of cell migration during development, but the mechanisms by which this is achieved are unclear. Here we show that activation of endogenous EphA2 kinase induces an inactive conformation of integrins and inhibits cell spreading, migration and integrin-mediated adhesion. Moreover, EphA2 is constitutively associated with focal-adhesion kinase (FAK) in resting cells. Within one minute after stimulation of EphA2 with its ligand, ephrin-A1, the protein tyrosine phosphatase SHP2 is recruited to EphA2; this is followed by dephosphorylation of FAK and paxillin, and dissociation of the FAK–EphA2 complex. We conclude that Eph kinases mediate some of their functions by negatively regulating integrins and FAK.
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Acknowledgements
We thank J.R. Sedor, S. Brady-Kalnay, M. Konieczkowski and J.R. Schelling for critical reading of the manuscript; R.L. Van Etten for antibody to LMW-PTP; and J.-L. Guan and J. Pessin for FAK and SHP2 expression plasmids. B.W. is supported by grants from the American Heart Association (grant 9806275), American Cancer Society (Cuyahoga Division), Department of the Army (grant PC970263) and NIH (grant P50 DK54178).
Correspondence and requests for materials should be addressed to B.W.
Supplementary information is available on Nature Cell Biology’s World-Wide Web site (http://cellbio.nature.com) or as paper copy from the London editorial office of Nature Cell Biology.
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EphA2 and EphB1 regulation of integrin-mediated cell adhesion: nonspecific stimulation versus specific inhibition is determined by ligand presentation (PDF 132 kb)
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Miao, H., Burnett, E., Kinch, M. et al. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2, 62–69 (2000). https://doi.org/10.1038/35000008
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DOI: https://doi.org/10.1038/35000008
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