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PNAS 96 (24): 13813-13818

Copyright © 1999 by the National Academy of Sciences.

Inaugural Article

BIOLOGICAL SCIENCES / CELL BIOLOGY

An Eph receptor regulates integrin activity through R-Ras

June X. Zou, Bingcheng Wang*, Matthew S. Kalo, Andreas H. Zisch{dagger}, Elena B. Pasquale, and Erkki Ruoslahti{ddagger}

Cancer Research Center, The Burnham Institute, La Jolla, CA 92037

Contributed by Erkki Ruoslahti

Accepted for publication September 17, 1999.

Abstract: The ability of integrins to mediate cell attachment to extracellular matrices and to blood proteins is regulated from inside the cell. Increased ligand-binding activity of integrins is critical for platelet aggregation upon blood clotting and for leukocyte extravasation to inflamed tissues. Decreased adhesion is thought to promote tumor cell invasion. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. Here we show that the Eph receptor tyrosine kinase, EphB2, can control integrin activity through R-Ras. Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. The R-Ras phosphorylation and loss of cell adhesion are causally related, because forced expression of an R-Ras variant resistant to phosphorylation at the critical site made cells unresponsive to the anti-adhesive effect of EphB2. This is an unusual regulatory pathway among the small GTPases. Reduced adhesiveness induced through the Eph/R-Ras pathway may explain the repulsive effect of the Eph receptors in axonal pathfinding and may facilitate tumor cell invasion and angiogenesis.

* Present address: Rammelkamp Center for Research, Metro-Health Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44109.

{dagger} Present address: Department of Materials and Institute for Biomedical Engineering, ETH Zurich and the University of Zurich, Moussonstrasse 18, CH-8044 Zurich, Switzerland.

{ddagger} To whom reprint requests should be addressed at: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: ruoslahti{at}burnham.org.

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